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Introduction: This review analyzes the efficacy of pneumococcal vaccinations in lung transplant patients before and after transplantation.Areas covered: This review addresses the risk for respiratory infections, in particular pneumococcal infections, in lung transplantation patients in the context of immunodeficiency and immunosuppressive medication. Vaccination is recommended to counteract the increased risk of pneumococcal infection, and the relevant guidelines are discussed in this review. The design of specific vaccination schedules is required because of the impaired antibody response in specific patient categories.Expert opinion: Lung transplantation candidates should be vaccinated with pneumococcal vaccines prior to transplantation. Currently, the 23-valent pneumococcal polysaccharide vaccine offers the broadest coverage, but the antibody response should be monitored. New generation pneumococcal conjugate vaccines with equally broad serotype coverage could be used in the future. During the post-transplantation period, the immune status of the patients should be monitored regularly, and vaccination should be repeated when indicated.

Because one of the functions of the immune system is to protect against tumors [1], the occurrence of cancer could be a reflection of an improperly functioning immune system. While this has been th...

C-C chemokine receptor 5 (CCR5) and polymorphisms in CCR5 gene are associated with sarcoidosis and Löfgren’s syndrome. Löfgren’s syndrome is an acute and usually self-remitting phenotype of sarcoidosis. We investigated whether the single nucleotide polymorphism (SNP) rs1799987 is associated with susceptibility for Löfgren’s syndrome and has an effect on CCR5 expression on monocytes and function of CCR5. A total of 106 patients with Löfgren’s syndrome and 257 controls were genotyped for rs1799987. Expression of CCR5 on monocytes was measured by flowcytometry. We evaluated calcium influx kinetics following stimulation upon N-formylmethionyl-leucyl-phenylalanine (fMLP) and macrophage inflammatory protein-1α (MIP-1α) on monocytes by measuring the median fluorescence intensity (MFI). The frequency of the G allele of rs1799987 was significantly higher in Löfgren’s syndrome than in healthy controls (p = 0.0015, confidence interval (CI) 1.22–2.32, odds ratio (OR) 1.680). Patients with a GG genotype showed higher CCR5 expression on monocytes than patients with the AA genotype (p = 0.026). A significantly (p = 0.027) lower count of patients with the GG genotype showed a calcium influx reaction to simulation upon MIP-1 α, compared with patients with the AA genotype. The rs1799987 G allele in CCR5 gene is associated with susceptibility to Löfgren’s syndrome and with quantitative and qualitative changes in CCR5, potentially effecting the inflammatory response.

Lung transplant patients are immunocompromised because of the medication they receive to prevent rejection, and as a consequence are susceptible to (respiratory) infections. Adequate vaccination strategies, including COVID-19 vaccination, are therefore needed to minimize infection risks.The international vaccination guidelines for lung transplant patients are reviewed, including the data on immunogenicity and effectivity of the vaccines. The impact on response to vaccination of the various categories of immunosuppressive drugs, used in the posttransplant period, on response to vaccination is described. A number of immunosuppressive and/or anti-inflammatory drugs also is used for controlling the immunopathology of severe COVID-19. Current available COVID-19 vaccines, both mRNA or adenovirus based are recommended for lung transplant patients.In order to improve survival and quality of life, infections of lung transplant patients should be prevented by vaccination. When possible, vaccination should start already during the pre-transplantation period when the patient is on the waiting list. Booster vaccinations should be given post-transplantation, but only when immunosuppression has been tapered. Vaccine design based on mRNA technology could allow the design of an array of vaccines against other respiratory viruses, offering a better protection for lung transplant patients.

Infection with Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) causes Coronavirus Disease 2019 (COVID-19), which has reached pandemic proportions. A number of effective vaccines have been produced, including mRNA vaccines and viral vector vaccines, which are now being implemented on a large scale in order to control the pandemic. The mRNA vaccines are composed of the Spike S1 protein encoding mRNA, incorporated in a lipid nanoparticle, stabilized by polyethylene glycol (PEG). mRNA vaccines are novel in many respects, including cellular uptake, the intracellular routing, processing, and secretion of the viral protein. Viral vector vaccines have incorporated DNA sequences encoding the SARS-CoV-2 Spike S1 protein into (attenuated) adenoviruses. The antigen presentation routes in MHC class I and class II, in relation to induction of virus neutralizing antibodies and cytotoxic T-lymphocytes will be reviewed. In rare cases, mRNA vaccines induce unwanted immune mediated side effects. mRNA based vaccines may lead to an anaphylactic reaction. This reaction may be triggered by PEG. The intracellular routing of PEG, and potential presentation in the context of CD1 will be discussed. Adenovirus vector based vaccines have been associated with thrombocytopenic thrombosis events. The anti-platelet factor 4 antibodies found in these patients could be generated due to conformational changes of relevant epitopes presented to the immune system.

Infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes Coronavirus Disease 2019 (COVID-19), which has reached pandemic proportions. A number of effective vaccines have been produced, including mRNA vaccines and viral vector vaccines, which are now being implemented on a large scale in order to control the pandemic. The mRNA vaccines are composed of viral Spike S1 protein encoding mRNA incorporated in a lipid nanoparticle and stabilized by polyethylene glycol (PEG). The mRNA vaccines are novel in many respects, including cellular uptake and the intracellular routing, processing, and secretion of the viral protein. Viral vector vaccines have incorporated DNA sequences, encoding the SARS-CoV-2 Spike protein into (attenuated) adenoviruses. The antigen presentation routes in MHC class I and class II, in relation to the induction of virus-neutralizing antibodies and cytotoxic T-lymphocytes, will be reviewed. In rare cases, mRNA vaccines induce unwanted immune mediated side effects. The mRNA-based vaccines may lead to an anaphylactic reaction. This reaction may be triggered by PEG. The intracellular routing of PEG and potential presentation in the context of CD1 will be discussed. Adenovirus vector-based vaccines have been associated with thrombocytopenic thrombosis events. The anti-platelet factor 4 antibodies found in these patients could be generated due to conformational changes of relevant epitopes presented to the immune system.

Introduction: Hairy cell leukemia (HCL) is a rare, indolent B-cell neoplasm. The classical variant of the disease is characterized by the BRAF V600E mutation, which is present in virtually all cases. How this mutation leads to the signs and symptoms of the disease is currently not known. Areas covered: This review explores the genetic background of HCL, especially the BRAF V600E driver mutation, but passenger mutations and their effects are also included. The clinical significance of BRAF mutations in other cancer types is discussed, as well as BRAF- induced senescence. An overview of the major forms of treatment of HCL (cytostatic drugs, specific BRAF inhibitors, B cell-specific antibodies) is given. Finally, possible mechanisms of the monocytopenia and hairy morphology so typical of this disease are discussed. Expert opinion: Although being a rare disease, HCL and its pathogenesis can yield important information about BRAF-related cancer metabolism. Many aspects of the disease are still unclear, but with the right resources, this could change. This can lead to a more efficient and specific treatment, thus leading to decreased morbidity.

Purpose of review Host defense against community-acquired pneumonia depends on an intact innate and acquired immune system. This review analyses the correlation between specific defects and polymorphisms of immunity genes with susceptibility for pneumonia. Recent findings Mutations in BTK, Bruton's tyrosine kinase, lead to X-linked agammaglobulinemia, a disease characterized by recurrent respiratory tract infections, including pneumonia. BTK inhibitors, which are used for treatment of leukemia, have pneumonia as side effect. Polymorphisms in B lymphocyte growth and differentiation factors, including IL-6 and IL-10, Fcg RIIa receptors, as well as genetic variants of ACE, angiotensin-converting enzyme, also are associated with increased susceptibility for pneumonia. Summary Delineation of underlying genetic defects and polymorphisms may add in diagnosis, therapy, and prognosis of community-acquired pneumonia. In case of humoral immunodeficiency, antibody replacement therapy may be indicated.

Introduction Polyneuropathy with immunoglobulin M monoclonal gammopathy (IgM-PNP) is associated with the presence of IgM antibodies against nerve constituents such as myelin associated glycoprotein (MAG) and gangliosides. Methods To test whether B-cell-stimulating cytokines are increased in IgM-PNP, we measured serum concentrations of 11 cytokines in 81 patients with IgM-PNP and 113 controls. Results Median interleukin (IL)-6 concentrations were higher in patients with IgM-PNP, and median IL-10 concentrations were higher in the subgroup with anti-MAG IgM antibodies. These serum concentrations were not increased in 110 patients with multifocal motor neuropathy. Discussion Median IL-6 and IL-10 serum concentrations differ between patients with anti-MAG neuropathy and other patients with IgM-PNP compared with healthy and neuropathy controls. These differences may indicate differences in immune-mediated disease mechanisms. Muscle Nerve 59:694-698, 2019.

A Gram-stain-positive, motile, rod-shaped, obligately anaerobic bacterium, designated FRIFIT, was isolated from human ileostoma effluent and characterized. On the basis of 16S rRNA gene sequence similarity, strain FRIFIT was most closely related to the species Romboutsia ilealis CRIBT (97.7 %), Romboutsia lituseburensis DSM 797(T) (97.6 %) and Romboutsia sedimentorum LAM201(T) (96.6 %). The level of DNA-DNA relatedness between strain FRIFIT and R. ilealis CRIBT was 13.9 +/- 3.3% based on DNA-DNA hybridization. Whole genome sequence-based average nucleotide identity between strain FRIFIT and closely related Romboutsia strains ranged from 78.4-79.1 %. The genomic DNA G+C content of strain FRIFIT was 27.8 mol%. The major cellular fatty acids of strain FRIFI T were saturated and unsaturated straight-chain C12-C19 fatty acids as well as cyclopropane fatty acids, with C-16:0 being the predominant fatty acid. The polar lipid profile comprised five phospholipids and six glycolipids. These results, together with differences in phenotypic features, support the proposal that strain FRIFIT represents a novel species within the genus Romboutsia, for which the name Romboutsia hominis sp. nov. is proposed. The type strain is FRIFIT (=DSM 28814(T) = KCTC 15553(T)).

Summary Unlike immunoglobulin (Ig)G pneumococcal polysaccharide (PnPS)‐antibodies, PnPS IgA and IgM‐antibodies are not routinely determined for the assessment of immunocompetence. It is not yet known whether an isolated inability to mount a normal IgM or IgA‐PnPS response should be considered a relevant primary antibody deficiency (PAD). We studied the clinical relevance of anti‐PnPS IgM and IgA‐assays in patients with suspected primary immunodeficiency in a large teaching hospital in ’s‐Hertogenbosch, the Netherlands. Serotype‐specific‐PnPS IgG assays were performed; subsequently, 23‐valent‐PnPS IgG assays (anti‐PnPS IgG assays), and later anti‐PnPS IgA and IgM assays, were performed in archived material (240 patients; 304 samples). Eleven of 65 pre‐ and six of 10 post‐immunization samples from good responders to PnPS serotype‐specific IgG testing had decreased anti‐PnPS IgA and/or IgM titres. Of these, three pre‐ and no post‐immunization samples were from patients previously classified as ‘no PAD’. Determination of anti‐PnPS IgA and IgM in addition to anti‐PnPS IgG did not reduce the need for serotype‐specific PnPS IgG testing to assess immunocompetence [receiver operating characteristic (ROC) analysis of post‐immunization samples: anti‐PnPS IgA + IgG area under the curve (AUC) = 0.80, 95% confidence interval (CI) = 0.63–0.97; anti‐PnPS IgM + IgG AUC 0.80, 95% CI = 0.62–0.98; anti‐PnPS IgA + IgG + IgM AUC = 0.71, 95% CI = 0.51–0.91; anti‐PnPS IgG AUC = 0.93, 95% CI = 0.85–1.00]. Our data show that patients classified as having an intact antibody response based on measurement of serotype‐specific PnPS IgG can still display impaired anti‐PnPS IgM and IgA responses, and that the additional measurement of anti‐PnPS IgA and IgM could not reduce the need for serotype‐specific IgG testing. Future studies are needed to investigate the clinical relevance of potential ‘specific IgA or IgM antibody deficiency’ in patients with recurrent airway infections in whom no PAD could be diagnosed according to the current definitions., Patients classified as having an intact PnPS IgG antibody response, still can display defective anti‐PnPS IgA and IgM responses. Whether ‘specific IgA or IgM antibody deficiency’ is a clinically relevant form of antibody deficiency should be investigated in future studies.

(1) Background: In the United Kingdom, Ireland, Iceland, France, Spain, Portugal, and Italy a subject participating in a (bio) medical experiment is termed a guinea pig. In Germany (Versuchskaninchen), The Netherlands, all of Scandinavia, and most of Eastern Europe, the term rabbit is used for such a subject. We have searched for potential differences in attitudes towards biomedical research by inhabitants of the respective European countries by making an analysis of frequency and motivation to participate in biomedical experiments on both sides of the European rabbit borderline. (2) Methods: We have performed an analysis of the use of experimental animals for research in European countries as well as country specific scientific output in PubMed indexed literature. Attitudes towards biomedical research in European countries was derived from EU questionnaires. (3) Results: In biomedical experiments with animals, more guinea pigs are used in laboratories in “rabbit countries” than in “guinea pig countries”. Inhabitants of “rabbit countries” have a higher participation rate in biomedical experiments and donation of blood than people from “guinea pig” countries. The reasons to participate in a medical experiment are not purely altruistic, especially in “rabbit countries”. (4) Conclusions: inhabitants of European countries in which a person who participates in a biomedical experiment is labeled as an (experimental) rabbit participate more in biomedical experiments as well as tissue and organ donation. Motives to do so are not just altruistic, because financial reasons also play a role.

Background Pneumococcal conjugate vaccination as well as pneumococcal polysaccharide vaccination are recommended for lung transplant candidates and recipients, but the combination of these vaccines has not been extensively studied in these specific populations. Methods Lung transplant candidates and recipients were vaccinated with a 13-valent pneumococcal conjugate vaccine, followed 8 weeks later by a pneumococcal polysaccharide vaccine. Pneumococcal antibody levels against 13 pneumococcal serotypes were measured and followed up after 1 year in the transplant recipients. These values were compared with a historical control group vaccinated with the polysaccharide vaccine alone. Results Twenty-five lung transplant candidates and 23 lung transplant recipients were included. For the majority of serotypes, there was no significant increase in antibody levels after additional vaccination with the polysaccharide vaccine in both patient groups. When compared with the historical control group, the antibody response in lung transplant recipients 1 year after vaccination did not seem to have improved by vaccination with both vaccines instead of the polysaccharide vaccine alone. Conclusions Serologic vaccination responses in lung transplant candidates and recipients were not improved by giving a 23-valent pneumococcal polysaccharide vaccine after a 13-valent pneumococcal conjugate vaccine. The benefit of this vaccination schedule in lung transplant recipients seems to differ from other immunocompromised populations. The optimal vaccination schedule for lung transplant candidates and recipients remains to be determined.

The neonatal period, during which the initial gut microbiota is acquired, is a critical phase. The healthy development of the infant's microbiome can be interrupted by external perturbations, like antibiotics, which are associated with profound effects on the gut microbiome and various disorders later in life. The aim of this study was to investigate the development of intestinal microbiota and the effect of antibiotic exposure during the first three months of life in term infants. Fecal samples were collected from healthy infants and infants who received antibiotics in the first week of life at one week, one month, and three months after birth. Microbial composition was analyzed using IS-pro and compared between antibiotics-treated and untreated infants. In total, 98 infants, divided into four groups based on feeding type and delivery mode, were analyzed. At one week of age, samples clustered into two distinct groups, which were termed “settler types”, based on their Bacteroidetes abundance. Caesarean-born infants belonged to the low-Bacteroidetes settler type, but vaginally-born infants were divided between the two groups. The antibiotics effect was assessed within a subgroup of 45 infants, vaginally-born and exclusively breastfed, to minimize the effect of other confounders. Antibiotics administration resulted in lower Bacteroidetes diversity and/ or a delay in Bacteroidetes colonization, which persisted for three months, and in a differential development of the microbiota. Antibiotics resulted in pronounced effects on the Bacteroidetes composition and dynamics. Finally, we hypothesize that stratification of children's cohorts based on settler types may reveal group effects that might otherwise be masked.

Introduction. Exhaled breath condensate (EBC) is a noninvasive method to collect samples from the respiratory tract. Usually, a thermoelectric cooling module is required to collect sufficient EBC volume for analyses. In here, we assessed the feasibility of cytokine and chemokine detection in EBC collected directly from the ventilator circuit without the use of a cooling module: swivel-derived exhaled breath condensate (SEBC). Methods. SEBC was prospectively collected from the swivel adapter and stored at -80°C. The objective of this study was to detect cytokines and chemokines in SEBC with a multiplex immunoassay. Secondary outcomes were to assess the correlation between cytokine and chemokine concentrations in SEBC and mechanical ventilation parameters, systemic inflammation parameters, and hemodynamic parameters. Results. Twenty-nine SEBC samples were obtained from 13 ICU patients. IL-1β, IL-4, IL-8, and IL-17 were detected in more than 90% of SEBC samples, and significant correlations between multiple cytokines and chemokines were found. Several significant correlations were found between cytokines and chemokines in SEBC and mechanical ventilation parameters and serum lactate concentrations. Conclusion. This pilot study showed that it is feasible to detect cytokines and chemokines in SEBC samples obtained without a cooling module. Despite small sample size, correlations were found between cytokines and chemokines in SEBC and mechanical ventilation parameters, as well as serum lactate concentrations. This simple SEBC collection method provides the opportunity to collect EBC samples in large prospective ICU cohorts.

The outcome of the first series of health claim applications for probiotics in Europe as evaluated by the European Food Safety Authority (EFSA) has, up to 2013 almost completely yielded negative results. All recent applications also have been rejected, including the latest on prevention of mastitis in breastfeeding mothers. In other developed countries, such as Switzerland, Japan and Canada, the health effects of probiotics, for which scientific evidence has been provided, can be communicated to potential consumers. The number of clinical trials with probiotics over recent years shows a trend to level off or even decline. At the same time, clinical research into the role of (gut) microbiota in a wide variety of diseases and conditions is booming. Ultimately, this may offer new indications for gut microbiota management by probiotics, prebiotics or other food supplements.

Cultivation-independent surveys have shown that the recently described genusRomboutsiawithin the familyPeptostreptococcaceaeis more diverse than previously acknowledged. The majority ofRomboutsia-associated 16S rRNA gene sequences have an intestinal origin, but the specific roles thatRomboutsiaspecies play in the digestive tract are largely unknown. The complete genomes of the human intestinal isolateRomboutsia hominisFRIFIT(DSM 28814) and the soil isolateRomboutsia lituseburensisA25KT(DSM 797) were sequenced. An evaluation of the common traits of this recently defined genus was done based on comparative genome analysis of the two strains together with the previously elucidated genome of the type speciesRomboutsia ilealisCRIBT. These analyses showed that the genusRomboutsiacovers a broad range of metabolic capabilities with respect to carbohydrate utilization, fermentation of single amino acids, anaerobic respiration and metabolic end products. Main differences between strains were found in their abilities to utilize specific carbohydrates, to synthesize vitamins and other cofactors, and their nitrogen assimilation capabilities. In addition, differences were found with respect to bile metabolism and motility-related gene clusters.

Background: Patients with recurrent respiratory tract infections and an impaired response to pneumococcal polysaccharide vaccination are diagnosed with a specific antibody deficiency. In adult patients with pneumococcal pneumonia an impaired antibody response to the infecting pneumococcal serotype can sometimes be found. It is unknown whether these patients are unable to produce an adequate anti-polysaccharide antibody response to pneumococcal vaccination after recovery.Case presentation: The authors describe a case of invasive pneumonia caused by Streptococcus pneumoniae serotype 9V in a previously healthy 35-year-old female. This patient did not produce serotype-specific antibodies against the infecting serotype during disease. After pneumococcal polysaccharide vaccination 3 months after recovery, she responded adequately to most other pneumococcal serotypes, but still had no response to the infecting serotype 9V. However, after 9 years (and prior to pneumococcal-conjugate vaccination) normal antibody levels against 9V were found. These antibody levels further increased after pneumococcal-conjugate vaccination.Conclusion: The authors believe that this case is the first description of a temporary deficient response to the infecting pneumococcal serotype in adults, while other reports with similar observations all involved children.

The effect of splenectomy on the incidence of infections and thromboembolisms has been investigated thoroughly. Nevertheless, the long-term effects of splenectomy on immunological profile and circulating blood counts have not been described before. To study such long-term effects, we analysed several parameters in splenectomised trauma patients and compared the results of this group ("otherwise healthy patients") to patients with a specific underlying disease. We measured platelet count, leukocytes and differential, lymphocyte subsets, serum levels of immunoglobulins, and complement pathways in 113 patients. Indications to perform a splenectomy were trauma (n = 42), Hodgkin lymphoma (n = 24), hereditary spherocytosis (n = 21), and immune thrombocytopenia (n = 26). In trauma patients lymphocytes and lymphocytes subsets were particularly elevated compared to normal population values. Splenectomised patients with Hodgkin lymphoma had significant lower numbers of T lymphocytes than trauma patients. Significant increases in platelets, leukocytes, and monocytes were observed in patients with hereditary spherocytosis. Occurrence of MBL genotype was different in ITP patients than in other splenectomised groups and the normal population. In splenectomised patients (> 4 years), platelet counts and lymphocyte subsets are increased which persist over time. As a result, these blood counts in splenectomised patients differ from reference values in the normal population.

Background and objective: Mortality after hospitalization with community-acquired pneumonia (CAP) is high, compared with age-matched controls. Available evidence suggests a strong link with cardiovascular disease. Our aim was to explore the prognostic value of high-sensitivity cardiac troponin T (cTnT) for mortality in patients hospitalized with CAP. Methods: CTnT level on admission was measured (assay conducted in 2015) in 295 patients hospitalized with CAP who participated in a randomized placebo-controlled double-blind trial on adjunctive dexamethasone treatment. Outcome measures were short- (30-day) and long-term (4.1-year) mortalities. Results: CTnT levels were elevated (≥14 ng/L) in 132 patients (45%). Pneumonia severity index (PSI) class was 4–5 in 137 patients (46%). Short- and long-term mortality were significantly higher in patients with elevated cTnT levels. cTnT level on admission combined with PSI classification was significantly better in predicting short-term mortality (area under the operating curve (AUC) = 0.903; 95% CI = 0.847–0.960), compared with PSI classification alone (AUC = 0.818; 95% CI = 0.717–0.919). An optimal cTnT cut-off level of 28 ng/L was independently associated with both short- and long-term mortality (OR = 21.9; 95% CI = 4.7–101.4 and 10.7; 95% CI = 5.0–22.8, respectively). Conclusion: Elevated cTnT level on admission is a strong predictor of short- and long-term mortalities in patients hospitalized with CAP.

Summary Community‐acquired pneumonia (CAP) is the leading infectious disease requiring hospitalization in the western world. Genetic variability affecting the host response to infection may play a role in susceptibility and outcome in patients with CAP. Mannose‐binding lectin (MBL) and l‐ficolin (l‐FCN) are two important activators of the complement system and they can enhance phagocytosis by opsonization. In a prospective cohort of 505 Dutch patients with CAP and 227 control participants we studied whether polymorphisms in the MBL (MBL2) and FCN (FCN2) genes influenced susceptibility and outcome. No difference in frequency of these genotypes was found between patients with CAP in general and controls. However, the +6424G>T single nucleotide polymorphism (SNP) in FCN2 was more common in patients with a Coxiella burnetii pneumonia (P = 0·014). Moreover, the haplotypes coding for the highest MBL serum levels (YA/YA and YA/XA) predisposed to atypical pneumonia (C. burnetii, Legionella or Chlamydia species or Mycoplasma pneumoniae) compared with controls (P = 0·016). Furthermore, patients with these haplotypes were more often bacteraemic (P = 0·019). It can therefore be concluded that MBL2 and FCN2 polymorphisms are not major risk factors for CAP in general, but that the +6424G>T SNP in the FCN2 gene predisposes to C. burnetii pneumonia. In addition, patients with genotypes corresponding with high serum MBL levels are at risk for atypical pneumonia, possibly caused by enhanced phagocytosis, thereby promoting cell entry of these intracellular bacteria.