Long-term oral antibiotic treatment : why, what, when and to whom?

Antibiotics are typically prescribed as short courses for acute infections, in order to reduce bacterial load, shift the balance in favour of host defences and thus help to overcome infection. Over the past decade, however, interest in the long-term anti-inflammatory and immunomodulatory effects of selected antibiotics has been on the increase. Since the clinical effectiveness of erythromycin was reported in diffuse panbronchiolitis in the 1980s, the use of macrolides has been adopted into many other chronic inflammatory airway diseases characterised by frequent exacerbations, including cystic fibrosis (CF), non-CF bronchiectasis, COPD, severe noneosinophilic asthma, bronchiolitis obliterans after lung transplantation and organising pneumonia. In this chapter, we discuss the indications and limitations of long-term macrolide treatment in these chronic respiratory conditions

Clinical Studies, Big Data, and Artificial Intelligence in Nephrology and Transplantation

In recent years, artificial intelligence has increasingly been playing an essential role in diverse areas in medicine, assisting clinicians in patient management. In nephrology and transplantation, artificial intelligence can be utilized to enhance clinical care, such as through hemodialysis prescriptions and the follow-up of kidney transplant patients. Furthermore, there are rapidly expanding applications and validations of comprehensive, computerized medical records and related databases, including national registries, health insurance, and drug prescriptions. For this Special Issue, we made a call to action to stimulate researchers and clinicians to submit their invaluable works and present, here, a collection of articles covering original clinical research (single- or multi-center), database studies from registries, meta-analyses, and artificial intelligence research in nephrology including acute kidney injury, electrolytes and acid–base, chronic kidney disease, glomerular disease, dialysis, and transplantation that will provide additional knowledge and skills in the field of nephrology and transplantation toward improving patient outcomes

The Impact of Tiny Organisms: Microbial Communities and Disease States

In the last decade, primarily through the use of sequencing, much has been learned about the trillions of microorganisms that reside in human hosts. These microorganisms play a wide range of roles including helping our immune systems develop, digesting our food, and protecting us from the invasion of pathogenic organisms. My thesis focuses on the characterization of fungal, viral, and bacterial communities in humans, investigating the use of defined microbial communities to cure diseases in animal models, and examining the effects of human microbiome modifications through fecal microbiota transfers. In the first part of this thesis, I use deep sequencing of ribosomal RNA gene tags to characterize the composition of the bacterial, fungal, and archaeal microbiota in pediatric patients with Inflammatory Bowel Disease and healthy controls. Archaeal reads were rare in the pediatric samples, whereas an abundant amount of fungal reads was recovered. Pediatric IBD was found to be associated with reduced diversity in both fungal and bacterial gut microbiota, and specific Candida taxa were increased in abundance in the IBD samples. I, then, describe my use of a variety of experimental and computational methods to study the viral communities of immune-compromised lung transplant recipients. Anelloviruses, circular, single-stranded DNA viruses, were found in all lung samples but were 56 times more abundant in samples from lung transplant recipients as compared to healthy controls or HIV+ subjects. In the third part of this thesis, I describe the use of defined microbial communities in mice, and its ability to reduce the production of ammonia long term and mitigate hepatic encephalopathy. This was shown to be true in both mice on a normal protein diet or a low protein diet. Last, I investigate the transfer of viral communities between humans through FMT and characterize features associated with efficient transmission. A case series where feces from a single donor were used to treat three children with ulcerative colitis was used for the analysis. Ultimately this work showed that multiple viral lineages do transfer between human individuals through fecal microbiota transplants, but in this case series none of the viruses were known to infect human cells. In this thesis, I elucidate numerous roles for the microbiome in pediatric patients with IBD and lung-transplant recipients, show exciting new finding about engineering the microbiota to help with hyperammonia, and finally investigate a possible limitation about using microbial communities as therapeutics. Together this body of work provides insights into the assemblage of tiny organisms that live within us, constantly contributing

The gut microbiota throughout paediatric haematopoietic stem cell transplantation

Haematopoietic stem cell transplantation is a curative procedure for a variety of underlying diagnoses including haematological, immunological and metabolic conditions such as acute myeloid leukaemia, Wiskott-Aldrich syndrome and Hurler’s syndrome, respectively. The procedure, which includes conditioning and a period of neutropaenia prior to the transplant engraftment, can lead to significant morbidity including viraemia, bacteraemia and Graft-versus-host disease. Gut microbiota has been extensively studied in adult haematopoietic stem cell transplantation. It is known to affect stem cell reconstitution and has been frequently linked to various clinical outcomes; however, paediatric studies are scarce. This work profiles the gut microbiota of paediatric patients undergoing haematopoietic stem cell transplantation at Great Ormond Street Hospital using both 16S rRNA sequencing and nuclear magnetic resonance spectroscopy. The initial chapter focuses on optimising the 16S rRNA methodology for this project. Subsequent chapters investigate the longitudinal gut microbiota and its dynamics throughout hospitalisation, as well as searches for clinical biomarkers at several time points throughout haematopoietic stem cell transplantation. We find that gut domination with a single taxon, specifically Enterococcus, Enterobacteriaceae, Streptococcus and Staphylococcus is common in this population. Additionally, we observe a loss of diversity around the time of the transplantation and that most patient microbiota profiles are unlike those of healthy individuals, even upon admission. We also identify three clusters within the data, revealing interesting cluster-switching patterns throughout transplantation and find that one cluster is linked to a higher risk of developing viraemia. We also find several biomarkers of viraemia and Graft-versus-host disease at baseline and around the time of engraftment, which may be indicative of overall gut health at that point. The final chapter profiles the faecal metabolome throughout haematopoietic stem cell transplantation and aims to broadly link the metabolome to the 16S data. We observe a loss of short chain fatty acids such as butyrate and acetate and increases in lactate and glucose throughout, which may be indicative of damaged gut epithelium and a loss of beneficial obligate anaerobes. Overall, these findings are indicative of a disruption of the host-microbe cross-talk

Harnessing the potential of multiomics studies for precision medicine in infectious disease

The field of infectious diseases currently takes a reactive approach and treats infections as they present in patients. Although certain populations are known to be at greater risk of developing infection (eg, immunocompromised), we lack a systems approach to define the true risk of future infection for a patient. Guided by impressive gains in omics technologies, future strategies to infectious diseases should take a precision approach to infection through identification of patients at intermediate and high-risk of infection and deploy targeted preventative measures (ie, prophylaxis). The advances of high-throughput immune profiling by multiomics approaches (ie, transcriptomics, epigenomics, metabolomics, proteomics) hold the promise to identify patients at increased risk of infection and enable risk-stratifying approaches to be applied in the clinic. Integration of patient-specific data using machine learning improves the effectiveness of prediction, providing the necessary technologies needed to propel the field of infectious diseases medicine into the era of personalized medicine

MICROBIAL PARTNERS IN HEALTH: BROADENING OUR UNDERSTANDING OF HOST-MICROBIOME RELATIONSHIPS

While microbes inhabit a wide array of environments, their ability to live within host tissue and become tolerated as part of a select microbial community is perhaps one of the most impressive feats of microbial resilience and survival. Host microbiome establishment and maintenance requires both host-microbe and microbe-microbe interactions. Among plant hosts, benefits from associated microbiomes are known to include improved growth, development and resistance to abiotic and biotic stresses. Mammalian microbiomes are known to improve host digestion, influence inflammation and even improve immune response to pathogens. While host-associated microbial communities across all domains of life are incredibly diverse, a growing number of studies are finding host-specific taxonomic trends, suggesting microbiome conservation and evolutionary selection. However, we have come to recognize that there is often functional redundancy between taxa. Therefore, investigative focus on microbiome composition potentially neglects pivotal and influential microbial players. Shifting focus to function over form creates the opportunity to tease apart the driving forces of unique microbiome constituents. This allows for identification of strains and genes of interest as well as microbial selections. To that end, here we describe the relationships between hosts and microbiomes as well as between microbes in two vastly different host systems (Figure 1.1). First, we suggest that plant root-associated Streptomyces isolates harboring genes encoding an enzyme and its co-factor are more tolerant of phenolic compounds generated by roots. Next, we address the capability of these Streptomyces isolates to employ their metabolic repertoires to influence the composition of the root microbiome. Finally, we define a previously under-described role for the gut microbiome in malaria immunology and suggest that gut microbial composition can modulate the severity of malarial disease. Together, these findings demonstrate the broad implications of microbiome composition across diverse hosts and environments, revealing unexplored opportunities for therapeutic interventions aimed at improving plant and human health

The Macrophages-Microbiota Interplay in Colorectal Cancer (CRC)-Related Inflammation: Prognostic and Therapeutic Significance

Tumor-associated macrophages (TAMs) are the main population of myeloid cells infiltrating solid tumors and the pivotal orchestrators of cancer-promoting inflammation. However, due to their exceptional plasticity, macrophages can be also key effector cells and powerful activators of adaptive anti-tumor immunity. This functional heterogeneity is emerging in human tumors, colorectal cancer (CRC) in particular, where the dynamic co-existence of different macrophage subtypes influences tumor development, outcome, and response to therapies. Intestinal macrophages are in close interaction with enteric microbiota, which contributes to carcinogenesis and affects treatment outcomes. This interplay may be particularly relevant in CRC, one of the most prevalent and lethal cancer types in the world. Therefore, both macrophages and intestinal microbiota are considered promising prognostic indicators and valuable targets for new therapeutic approaches. Here, we discuss the current understanding of the molecular circuits underlying the interplay between macrophages and microbiota in CRC development, progression, and response to both conventional therapies and immunotherapies

The future of affordable cancer immunotherapy

The treatment of cancer was revolutionized within the last two decades by utilizing the mechanism of the immune system against malignant tissue in so-called cancer immunotherapy. Two main developments boosted cancer immunotherapy: 1) the use of checkpoint inhibitors, which are characterized by a relatively high response rate mainly in solid tumors; however, at the cost of serious side effects, and 2) the use of chimeric antigen receptor (CAR)-T cells, which were shown to be very efficient in the treatment of hematologic malignancies, but failed to show high clinical effectiveness in solid tumors until now. In addition, active immunization against individual tumors is emerging, and the first products have reached clinical approval. These new treatment options are very cost-intensive and are not financially compensated by health insurance in many countries. Hence, strategies must be developed to make cancer immunotherapy affordable and to improve the cost-benefit ratio. In this review, we discuss the following strategies: 1) to leverage the antigenicity of “cold tumors” with affordable reagents, 2) to use microbiome-based products as markers or therapeutics, 3) to apply measures that make adoptive cell therapy (ACT) cheaper, e.g., the use of off-the-shelf products, 4) to use immunotherapies that offer cheaper platforms, such as RNA- or peptide-based vaccines and vaccines that use shared or common antigens instead of highly personal antigens, 5) to use a small set of predictive biomarkers instead of the “sequence everything” approach, and 6) to explore affordable immunohistochemistry markers that may direct individual therapies

Einfluss der Kolonisation mit therapieresistenten Krankheitserregern bei Patienten mit Mukoviszidose auf die Überlebensrate nach Lungentransplantation (LUTX)

Einleitung: Die Lungentransplantation ist eine Therapieoption bei Patienten mit fortgeschrittener Mukoviszidose. Da die Anzahl an Spenderorganen begrenzt ist, erfolgt die Auswahl und Priorisierung geeigneter Kandidaten anhand der Dringlichkeit und der Erfolgsaussichten der LUTX. Die chronische Kolonisationen mit therapieresistenten Erregern wird als Risikofaktor angesehen, hierzu gibt es jedoch nur wenige Daten. Methoden: 361 LUTX von 10/1995 bis 08/2020 infolge verschiedener Grund-erkrankungen wurden in die gesamte Studie eingeschlossen. 69 Mukoviszidose-Patienten wurden bezüglich einer Kolonisation mit einem multiresistenten Pseudomonas aeruginosa vor LUTX in 2 Gruppen unterteilt (ohne und mit Resistenz gegen 3 oder 4 Antibiotikagruppen, 3MRGN/4MRGN). Es wurden multivariable Überlebenszeitanalysen unter Berücksichtigung verschiedener Prädiktoren (präoperative, Spenderdaten, klinischer Verlauf) durchgeführt. Ergebnisse: In der Überlebenzzeitanalyse hatte die Gruppe mit 3MRGN/4MRGN ein schlechteres Überleben (P = 0.048). Die multivariable Analyse zeigte, dass eine Re-TX (P = 0.023, HR = 2.303), weibliches Geschlecht (P = 0.019, HR = 2.244) und die therapieresistente Kolonisation (P = 0.036, HR = 2.376) die Überlebenszeit verschlechterten, der Lungen-allokations-Score (LAS) war hingegen nicht signifikant (P = 0.186). Eine Therapie mit ECMO/ECCO2R war mit einem erhöhten Sterberisiko verbunden (P = 0.014, HR = 2.929) und führte zur Insignifikanz der multiresistenten Kolonisation (P = 0.197). Das Spenderorgan beeinflusste die Überlebenszeit nicht signifikant. Die Ko-Kokolonisation mit Aspergillus fumigatus erhöhte das Sterberisiko der Gruppe mit 3MRGN/4MRGN (P = 0.037, HR = 2.150). Das Versterben an einer Infektion ergab keinen signifikanten Unterschied zwischen den beiden Gruppen. Schlussfolgerung: Eine umfassende Berücksichtigung der präoperativen Kovariablen ist bei Mukoviszidose-Patienten mit Kolonisation von therapieresistenten Krankheitserregern entscheidend für eine erfolgreiche LUTX, ein extrakorporales Therapieverfahren vor LUTX war in dieser Studie der lebensbegrenzendste Faktor.Introduction: Lung transplantation is a therapy option for patients with advanced cystic fibrosis. In view of the limited number of donor organs the selection and prioritization of suitable recipients is based upon urgency and success of LUTX. The chronic colonizations with therapy resistant pathogens is considered to be a risk factor, however there are only few data available. Methods: 361 lung transplantations between 10/1995 and 08/2020 due to different underlying pulmonary diseases were included in the entire analysis. 69 cystic fibrosis patients were divided in two groups regarding colonization with multiresistent Pseudomonas aeruginosa before LUTX (without or with resistance to 3 or 4 antibiotic groups, 3MRGN/4MRGN). Multivariable survival time analyses were performed considering various predictors (preoperative, donor data, clinical course). Results: In the survival time analysis the group with 3MRGN/4MRGN had a poorer survival (P = 0.048). The multivariable analysis showed, that a Re-TX (P = 0.023, HR = 2.303), female gender (P = 0.019, HR = 2.244) and the multi- resistant colonization (P = 0.036, HR = 2.376) was associated with a poorer survival time, while the Lung Allocation Score (LAS) was not significant (P = 0.186). A therapy with ECMO/ECCO2R had a high risk of death (P = 0.014. HR = 2.929) and it led to an insignificancy of multiresistant colonization (P = 0.197). Donor characteristics did not affect the survival time. The co-colonization with Aspergillus fumigatus increased the mortality risk of the group with 3MRGN/4MRGN (P = 0.037, HR = 2.150). Concerning dying from infection there was not a significant group difference. Conclusions: A comprehensive consideration of the preoperative covariables in cystic fibrosis patients with therapy resistant colonizations is crucial for successful lung transplantation, an extracorporal therapy procedure before LUTX was the most life-limiting factor in this study