The NLRP3 Inflammasome: Relevance in Solid Organ Transplantation

The NOD, LRR, and pyrin domain-containing 3 (NLRP3) protein has been established as a central component of the inflammasome and regulates the inflammatory response to a myriad of environmental, microbial, and endogenous danger stimuli. Assembly of the NLRP3 inflammasome results in the cleavage and activation of caspase-1, in turn causing release of the pro-inflammatory interleukins 1-beta and 18. This activation response, while crucial to coordinated innate immune defense, can be aberrantly activated by the likes of cell-free DNA, and cause significant autoimmune pathology. Complications of autoimmunity induced by aberrant NLRP3 inflammasome activation have a great degree of mechanistic crossover with alloimmune injury in solid organ transplant, and stratagems to neutralize NLRP3 inflammasome activation may prove beneficial in solid organ transplant management. This article reviews NLRP3 inflammasome biology and the pathology associated with its hyperactivation, as well as the connections between NLRP3 inflammasome activation and allograft homeostasis.

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Cytomegalovirus in Solid Organ Transplant Recipients: Clinical Updates, Challenges and Future Directions

Current Pharmaceutical Design ◽

10.2174/1381612826666200531152901 ◽

2020 ◽

Vol 26 (28) ◽

pp. 3497-3506

Author(s):

Raymund R. Razonable

Keyword(s):

Organ Transplantation ◽

Solid Organ Transplantation ◽

Organ Transplant ◽

Solid Organ Transplant ◽

Solid Organ ◽

Transplant Recipients ◽

Cmv Infection ◽

Future Directions ◽

Prevention And Treatment ◽

Solid Organ Transplant Recipients

Cytomegalovirus is the classic opportunistic infection after solid organ transplantation. This review will discuss updates and future directions in the diagnosis, prevention and treatment of CMV infection in solid organ transplant recipients. Antiviral prophylaxis and pre-emptive therapy are the mainstays of CMV prevention, but they should not be mutually exclusive and each strategy should be considered depending on a specific situation. The lack of a widely applicable viral load threshold for diagnosis and preemptive therapy is emphasized as a major factor that should pave the way for an individualized approach to prevention. Valganciclovir and intravenous ganciclovir remain as drugs of choice for CMV management, and strategies for managing drug-resistant CMV infection are enumerated. There is increasing use of CMV-specific cell-mediated immune assays to stratify the risk of CMV infection after solid organ transplantation, and their potential role in optimizing CMV prevention and treatment efforts is discussed.

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Exploring the Epidemiology of Cancer after Solid Organ Transplantation (EpCOT): an observational cohort study

BMJ Open ◽

10.1136/bmjopen-2020-043731 ◽

2021 ◽

Vol 11 (4) ◽

pp. e043731

Author(s):

Adnan Sharif ◽

Javeria Peracha ◽

David Winter ◽

Raoul Reulen ◽

Mike Hawkins

Keyword(s):

Organ Transplantation ◽

Record Linkage ◽

Solid Organ Transplantation ◽

Organ Transplant ◽

Solid Organ Transplant ◽

Study Cohort ◽

Solid Organ ◽

Post Transplantation ◽

Increased Risk ◽

Risk Of Cancer

IntroductionSolid organ transplant patients are counselled regarding increased risk of cancer (principally due to their need for lifelong immunosuppression) and it ranks as one of their biggest self-reported worries. Post-transplantation cancer is common, associated with increased healthcare costs and emerging as a leading cause of post-transplant mortality. However, epidemiology of cancer post-transplantation remains poorly understood, with limitations including translating data from different countries and national data being siloed across different registries and/or data warehouses.Methods and analysisStudy methodology for Epidemiology of Cancer after Solid Organ Transplantation involves record linkage between the UK Transplant Registry (from NHS Blood and Transplant), Hospital Episode Statistics (for secondary care episodes from NHS Digital), National Cancer Registry (from cancer registration data hosted by Public Health England) and the National Death Registry (from NHS Digital). Deterministic record linkage will be conducted by NHS Digital, with a fully anonymised linked dataset available for analysis by the research team. The study cohort will consist of up to 85 410 solid organ transplant recipients,who underwent a solid organ transplant in England between 1 January 1985 and 31 December 2015, with up-to-date outcome data.Ethics and disseminationThis study has been approved by the Confidentiality Advisory Group (reference: 16/CAG/0121), Research Ethics Committee (reference: 15/YH/0320) and Institutional Review Board (reference: RRK5471). The results of this study will be presented at national and international conferences, and manuscripts with results will be submitted for publication in high-impact peer-reviewed journals. The information produced will also be used to develop national evidence-based clinical guidelines to inform risk stratification to enable risk-based clinical follow-up.Trial registration numberNCT02991105.

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Viral Enteritis in Solid-Organ Transplantation

Viruses ◽

10.3390/v13102019 ◽

2021 ◽

Vol 13 (10) ◽

pp. 2019

Author(s):

Anum Abbas ◽

Andrea J. Zimmer ◽

Diana Florescu

Keyword(s):

Solid Organ Transplantation ◽

Organ Transplant ◽

Solid Organ Transplant ◽

Solid Organ ◽

Transplant Recipients ◽

Post Transplantation ◽

Organ Transplant Recipients ◽

Increased Risk ◽

Viral Enteritis ◽

Solid Organ Transplant Recipients

Solid organ transplant recipients are at increased risk for infections due to chronic immunosuppression. Diarrhea is a commonly encountered problem post transplantation, with infectious causes of diarrhea being a frequent complication. Viral infections/enteritides in solid organ transplant recipients often result from frequently encountered pathogens in this population such as cytomegalovirus, adenovirus, and norovirus. However, several emerging viral pathogens are increasingly being recognized as more sensitive diagnostic techniques become available. Treatment is often limited to supportive care and reduction in immunosuppression, though antiviral therapies mayplay a role in the treatment in certain diseases. Viral enteritis is an important entity that contributes to morbidity and mortality in transplant recipients.

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Rashes associated with transplantations

Paediatric Dermatology ◽

10.1093/med/9780198821304.003.0039 ◽

2020 ◽

pp. 535-538

Keyword(s):

Fungal Infections ◽

Solid Organ Transplantation ◽

Organ Transplant ◽

Solid Organ Transplant ◽

Host Immunity ◽

Solid Organ ◽

Graft Versus Host ◽

Gingival Hypertrophy ◽

Life Threatening ◽

Transplant Complications

Dermatological manifestations following transplantation are common but important to recognize and diagnose since they may be severe and life-threatening if not adequately and promptly treated. This chapter provides a systematic overview of the types of skin disease that may be encountered in children that have received a haematological or solid organ transplant. Complications relating to immunosuppression include an increased susceptibility to bacterial, viral, and fungal infections which may be significantly more virulent and hazardous in the context of reduced host immunity. Immune suppressant drugs may also cause drug rashes and aesthetic complications such as acne, hypertrichosis, or gingival hypertrophy, as well as longer-term risks from the development of malignancy. It is also important to recognize the range of mucocutaneous signs of acute and chronic graft versus host disease following bone marrow and solid organ transplantation which, again, may be severe and associated with significant morbidity and mortality.

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The Roles of Endoplasmic Reticulum in NLRP3 Inflammasome Activation

Cells ◽

10.3390/cells9051219 ◽

2020 ◽

Vol 9 (5) ◽

pp. 1219 ◽

Cited By ~ 3

Author(s):

Yang Zhou ◽

Zhizi Tong ◽

Songhong Jiang ◽

Wenyan Zheng ◽

Jianjun Zhao ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Nlrp3 Inflammasome ◽

Critical Role ◽

Immune Defense ◽

Inflammasome Activation ◽

Nucleotide Binding Domain ◽

Cholesterol Trafficking ◽

Pyrin Domain ◽

Nlrp3 Inflammasome Activation ◽

Molecular Patterns

The NLRP3 (nucleotide-binding domain, leucine-rich-repeat-containing family, pyrin domain-containing 3) inflammasome senses pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), and activates caspase-1, which provokes release of proinflammatory cytokines such as interleukin-1β (IL-1β) and IL-18 as well as pyroptosis to engage in innate immune defense. The endoplasmic reticulum (ER) is a large and dynamic endomembrane compartment, critical to cellular function of organelle networks. Recent studies have unveiled the pivotal roles of the ER in NLRP3 inflammasome activation. ER–mitochondria contact sites provide a location for NLRP3 activation, its association with ligands released from or residing in mitochondria, and rapid Ca2+ mobilization from ER stores to mitochondria. ER-stress signaling plays a critical role in NLRP3 inflammasome activation. Lipid perturbation and cholesterol trafficking to the ER activate the NLRP3 inflammasome. These findings emphasize the importance of the ER in initiation and regulation of the NLRP3 inflammasome.

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Challenges in the Diagnosis and Management of Bacterial Lung Infections in Solid Organ Recipients: A Narrative Review

International Journal of Molecular Sciences ◽

10.3390/ijms21041221 ◽

2020 ◽

Vol 21 (4) ◽

pp. 1221 ◽

Cited By ~ 1

Author(s):

Manuela Carugati ◽

Letizia Morlacchi ◽

Anna Peri ◽

Laura Alagna ◽

Valeria Rossetti ◽

...

Keyword(s):

Respiratory Infections ◽

Solid Organ Transplantation ◽

Organ Transplant ◽

Solid Organ Transplant ◽

Narrative Review ◽

Solid Organ ◽

Transplant Recipients ◽

Organ Transplant Recipients ◽

Diagnosis And Management ◽

Solid Organ Transplant Recipients

Respiratory infections pose a significant threat to the success of solid organ transplantation, and the diagnosis and management of these infections are challenging. The current narrative review addressed some of these challenges, based on evidence from the literature published in the last 20 years. Specifically, we focused our attention on (i) the obstacles to an etiologic diagnosis of respiratory infections among solid organ transplant recipients, (ii) the management of bacterial respiratory infections in an era characterized by increased antimicrobial resistance, and (iii) the development of antimicrobial stewardship programs dedicated to solid organ transplant recipients.

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The Immunology of SARS-CoV-2 Infection and Vaccines in Solid Organ Transplant Recipients

Viruses ◽

10.3390/v13091879 ◽

2021 ◽

Vol 13 (9) ◽

pp. 1879

Author(s):

Dominika Dęborska-Materkowska ◽

Dorota Kamińska

Keyword(s):

Solid Organ Transplantation ◽

Organ Transplant ◽

Solid Organ Transplant ◽

Cell Mediated Immunity ◽

Solid Organ ◽

Transplant Recipients ◽

Therapeutic Approaches ◽

Current State ◽

Severe Infections ◽

Main Component

Since its outbreak in December 2019, the coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), led to an enormous rise in scientific response with an excess of COVID-19-related studies on the pathogenesis and potential therapeutic approaches. Solid organ transplant (SOT) recipients are a heterogeneous population with long-lasting immunosuppression as a joining element. Immunocompromised patients are a vulnerable population with a high risk of severe infections and an increased infection-related mortality rate. It was postulated that the hyperinflammatory state due to cytokine release syndrome during severe COVID-19 could be alleviated by immunosuppressive therapy in SOT patients. On the other hand, it was previously established that T cell-mediated immunity, which is significantly weakened in SOT recipients, is the main component of antiviral immune responses. In this paper, we present the current state of science on COVID-19 immunology in relation to solid organ transplantation with prospective therapeutic and vaccination strategies in this population.

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A case series of non-valvular cardiac aspergillosis in critically ill solid organ transplant and non-transplant patients and systematic review

Journal of the Intensive Care Society ◽

10.1177/1751143720936821 ◽

2020 ◽

pp. 175114372093682

Author(s):

Annalan MD Navaratnam ◽

Mohammad Al-Freah ◽

Anna Cavazza ◽

Georg Auzinger

Keyword(s):

Systematic Review ◽

Intensive Care ◽

Critically Ill ◽

High Mortality ◽

Gall Stone ◽

Solid Organ Transplantation ◽

Organ Transplant ◽

Solid Organ Transplant ◽

Solid Organ ◽

Transplant Patients

Introduction Non-valvular cardiac aspergillosis is a rare infection of the pericardium, myocardium or endocardium and is associated with a high mortality. There is a paucity of reports of non-valvular cardiac aspergillosis in critically ill and solid organ transplant (SOT) patients. The majority of cases have been reported in haemato-oncology patients, some of whom have undergone a bone marrow transplant. Objectives We describe four cases affected by non-valvular cardiac aspergillosis in the intensive care setting including a systematic review of this extremely rare infection which is associated with high mortality. Results All four-patients died but presented with varying clinical, radiological and microbiological evidence of the disease. Three patients presented following complications after solid organ transplantation, two in the context of acute liver failure and emergency liver transplant and one several years after a double lung transplant. The last patient presented with necrotising gall stone pancreatitis, multi-organ failure and subsequently a prolonged intensive care unit (ICU) stay. On review of the literature, January 1955 to July 2019, 45 cases were identified, with different risk factors, clinical and radiological manifestations, treatment regimen and outcome. Conclusion Antemortem diagnosis of cardiac aspergillosis is difficult and rare, with no cases reporting positive blood culture results. Galactomannan serology has poor sensitivity in solid organ transplant patients, further reduced by prophylactic antimicrobial treatment, which is common in the ICU setting especially post-transplant patients. Due to the scarcity of cases, treatment is extrapolated from invasive aspergillosis management, with emphasis on early treatment with combination therapy.

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Infections in the solid-organ transplant recipients

Ukrainian Journal of Nephrology and Dialysis ◽

10.31450/ukrjnd.2(70).2021.08 ◽

2021 ◽

pp. 64-76

Author(s):

Manal El Said

Keyword(s):

Solid Organ Transplantation ◽

Organ Transplant ◽

Organ Donor ◽

Solid Organ Transplant ◽

Molecular Techniques ◽

Solid Organ ◽

Transplant Recipients ◽

Antimicrobial Drugs ◽

Organ Transplant Recipients ◽

Solid Organ Transplant Recipients

The advancement in the field of transplant has led to the increasing number of solid-organ transplant recipients (SOTRs). This success leads to novel confronts in communicable infections, which are compound by the emergence of newly contagious and antimicrobial drugs resistant microorganisms. The prevention of infections is a cornerstone of any modern solid organ transplantation program. Understanding the fundamentals of these infections with early detection is crucial for improving the outcomes of such patients and lowers the probable extra complications. The probability of critical infections in SOTRs is established by relations between the patient’s epidemiological exposures and the net condition of immune repression. A timeline was formed to build up a discrepancy diagnosis of infection in SORTs. The improvement in screening, the investigations including imaging and molecular techniques and prophylactic intervention protocols, has made it promising to limit the penalty of infections and act towards better patient endurance. Pre-transplant screening of the prospective organ donor and recipient provides a chance to evaluate the viability and wellbeing of transplantation, to decide the prophylaxis and protective approaches developed post-transplant, to find out and entirely treat active infection in the possible recipient proceeding to transplant, to renovate the vaccination condition of the potential recipient.

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Entrustable professional activities for pharmacy students: A primer for solid organ transplant preceptors

American Journal of Health-System Pharmacy ◽

10.1093/ajhp/zxab320 ◽

2021 ◽

Author(s):

Alicia Lichvar ◽

Mary Moss Chandran ◽

Vincent Do ◽

Trisann Rendulic ◽

Amanda Szczepanik ◽

...

Keyword(s):

Patient Care ◽

Organ Transplantation ◽

Solid Organ Transplantation ◽

Organ Transplant ◽

Solid Organ Transplant ◽

Pharmacy Students ◽

Entrustable Professional Activities ◽

Solid Organ ◽

Professional Activities ◽

Specialty Practice

Abstract Disclaimer In an effort to expedite the publication of articles , AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. Purpose The role of a solid organ transplant pharmacist is multifaceted and translates to diverse experiential and elective learning experiences that can be provided to pharmacy learners. Here we provide a guide to integrating pharmacy students into patient care and other pharmacist activities in solid organ transplantation. Summary Thoughtful incorporation of learners into clinical practice and clinical research creates a positive learning environment for pharmacy students that can foster the development of core skills necessary for students to become “practice-ready” and “team-ready” pharmacy graduates and can equip them with valuable skills to incorporate into the specialty practice areas and careers they pursue. To help develop these educational experiences, attention to the list of core entrustable professional activities (EPAs) established by the American Association of Colleges of Pharmacy can help create a rich environment of learning with carefully cultivated tasks. Furthermore, learners can serve as transplant pharmacist extenders to assist in overall patient care and multidisciplinary involvement on the transplant team. This article serves as a “how-to” guide for applying the EPA framework to integrating pharmacy students in patient care and other pharmacist activities in solid organ transplantation and other specialty practice areas. Conclusion As pharmacy preceptors design and operationalize their teaching to incorporate EPAs, they can benefit from recommendations tailored to specialty practice areas such as solid organ transplantation. Students may start and finish these experiences at different EPA levels, but continuance of training will allow them to achieve the final EPA level across the 6 EPA domains.

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