Prophylaxis of invasive mycoses in solid organ transplantation

Solid organ transplantation is emerging as a lifesaving procedure for increasing numbers of patients, and invasive fungal infections are a significant cause of mortality and morbidity for patients undergoing such procedures. Risks for developing these infections are continuing to evolve, leading to shifts in the epidemiology of invasive mycoses occurring after transplantation. Targeting preventive efforts to select solid organ transplantation groups at highest risk for invasive fungal infections is critical to optimizing prophylaxis strategies. The epidemiology of posttransplantation fungal infections, antifungal drug interactions and side effects, and new diagnostic capabilities should be considered when choosing an approach to antifungal prophylaxis for this population.     

Adult Hyperglycemic Crisis: A Review and Perspective

Hyperglycemic crisis, which includes Diabetic Ketoacidosis and Hyperglycemic Hyperosmolar State, is a common diagnosis in high acuity hospital units and admission rates continue to increase despite preventive strategies. While diabetic ketoacidosis remains a common cause of death in children and adolescents with type 1 diabetes, in adults reported mortality is variable and depends on the severity of metabolic derangement and the presence of other acute and chronic conditions. Hyperosmolar hyperglycemic state, and the overlap syndrome of hyperosmolar ketoacidosis, have a higher overall mortality though outcomes are improving. We discuss the diagnosis, epidemiology, and management strategies with particular reference to commonly encountered pitfalls in care and provide an updated perspective on the shifts in the epidemiology and novel management strategies for these important disorders.     

Epidemiology and control of nosocomial viral infections

The impact of nosocomial viral disease, in terms of morbidity, mortality, and health care expenditures, should not be underestimated. Respiratory viruses, in particular, account for a substantial proportion of all nosocomial infections, especially among pediatric patients and the institutionalized elderly. The immunocompromised, very young, and chronically ill patients in hospitals are unusually vulnerable to serious viral illness. The emerging technology of rapid viral diagnosis will allow more timely and accurate recognition of viral infections, even in the smaller hospital with limited laboratory resources. Early recognition of viral diseases should, in turn, permit us to institute, and further evaluate, specific measures for their control. Appreciation of the epidemiology and transmission of these viruses will provide the framework for successful infection control strategies.     

Advances and challenges in management of invasive mycoses

Invasive mycoses pose a major diagnostic and therapeutic challenge. Advances in antifungal agents and diagnostic methods offer the potential for improved outcomes in patients with these infections, which are often lethal. Many fungal pathogens occur almost exclusively in opportunistic settings--in the immunocompromised host--and these infections are the focus of this review. Several areas of ongoing challenge remain, including the emergence of resistant organisms and the absence of reliable markers for early identification of patients at risk of developing invasive fungal disease. This Seminar reviews the changing epidemiology of invasive mycoses, new diagnostic methods, and recent therapeutic options and current management strategies for these opportunistic pathogens.     

Infection control in the ICU.

Nosocomial infections (NIs) now concern 5 to 15% of hospitalized patients and can lead to complications in 25 to 33% of those patients admitted to ICUs. The most common causes are pneumonia related to mechanical ventilation, intra-abdominal infections following trauma or surgery, and bacteremia derived from intravascular devices. This overview is targeted at ICU physicians to convince them that the principles of infection control in the ICU are based on simple concepts and that the application of preventive strategies should not be viewed as an administrative or constraining control of their activity but, rather, as basic measures that are easy to implement at the bedside. A detailed knowledge of the epidemiology, based on adequate surveillance methodologies, is necessary to understand the pathophysiology and the rationale of preventive strategies that have been demonstrated to be effective. The principles of general preventive measures such as the implementation of standard and isolation precautions, and the control of antibiotic use are reviewed. Specific practical measures, targeted at the practical prevention and control of ventilator-associated pneumonia, sinusitis, and bloodstream, urinary tract, and surgical site infections are detailed. Recent data strongly confirm that these strategies may only be effective over prolonged periods if they can be integrated into the behavior of all staff members who are involved in patient care. Accordingly, infection control measures are to be viewed as a priority and have to be integrated fully into the continuous process of improvement of the quality of care.     

Mother-to-child transmission of HIV: A global perspective

HIV-1 infection is a significant global source of childhood morbidity and mortality, and mother-to-child transmission (MTCT) is the major mode of infection. Research over the past two decades has improved our understanding of the pathogenesis of MTCT and pediatric HIV-1 infection, lending to the development of effective preventive and therapeutic strategies. However, successful implementation of these strategies has been limited in resource-constrained settings, where the majority of new pediatric HIV infections now occur. Continued efforts are necessary to better understand MTCT and to refine preventive and therapeutic strategies to allow their successful implementation in the most needed places.     

Fungal infections in the recipients of solid organ transplantation

The advent of effective antibacterial and antiviral prophylatic and therapeutic strategies has led to the emergence of opportunistic mycoses as a principal cause of infection-related mortality in organ transplant recipients. Candida and Aspergillus species have accounted for most invasive fungal infections in organ transplant recipients. Epidemiologic trends within the last decade, however, are notable for the emergence of mycelial fungi other than Aspergillus as increasingly important pathogens in these patients. This article reviews the epidemiology, clinical manifestations, pathogenetic basis, diagnosis, and management of invasive fungal infections after organ transplantation in context of emerging trends and new developments in these areas.     

Legionellosis in Transplantation

Legionella species are emerging opportunistic pathogens in hematopoietic stem cell and solid organ transplant recipients, associated with significant morbidity and mortality. The clinical and radiological features of Legionella infections can mimic other opportunistic pathogens in these profoundly immunocompromised patients. Diagnosis in transplant patients is challenging as non-pneumophila Legionella infections, for which these patients are at risk, cannot be identified using the urinary antigen test. Changes in management of transplant recipients and changes in Legionella epidemiology suggest that the number of transplant patients potentially exposed to Legionella spp. may be on the rise. Yet, evidence-based, transplant-specific guidelines for managing and preventing Legionella infections are not currently available. In this article, we review the epidemiology, clinical features, diagnostic challenges, treatment options, and preventive strategies of Legionella infections in these high-risk patient populations.     

New challenges for mathematical and statistical modeling of HIV and hepatitis C virus in injecting drug users

Injecting drug users are not only driving blood-borne transmission of HIV and hepatitis C virus but also likely drive sexual transmission of HIV in large parts of the world. Mathematical and statistical modeling can provide important insights in these epidemiological processes and on the potential impact of interventions but have been little used to date. This review aims to discuss the potential areas of application of modeling in the field of viral infections in injecting drug users. After reviewing key examples of published modeling work on HIV and hepatitis C virus in injecting drug users, we discuss recent developments in the epidemiology, diagnosis, treatment and prevention of these infections. In particular, new methods for the diagnosis of early HIV infection, new antivirals for a more effective treatment of HIV, hepatitis B and hepatitis C virus infections, new concepts in design and surveillance of interventions for drug users and increasing possibilities of molecular typing of pathogens are changing the questions and decisions for public health policy makers who deal with drug-related infectious diseases. Research including mathematical modeling is needed to understand the impact of new diagnostic tools, new treatment options and combined intervention strategies on the epidemiology of viral infections in injecting drug users. Methodological advances in mathematical modeling are required to adequately approach some of the ensuing research questions. Modeling has much to offer for solving urgent policy questions, but current levels of funding in modeling research are insufficient and need to be scaled up to make better use of these possibilities.     

Bacterial infection-related morbidity and mortality in cirrhosis

OBJECTIVES: Bacterial infections are acknowledged causes of morbidity and mortality in cirrhotic patients; yet, apart from spontaneous bacterial peritonitis, other infection issues have been understudied. We evaluated the existing medical data on infectious risks and related preventive and treatment data for cirrhotic patients. METHODS: Medical literature search through MEDLINE, using a variety of keywords focused on: (a) immunodeficiency parameters of cirrhosis and attempts at therapeutic reversal, (b) relative incidence of various focal infections and implications for prevention, and (c) specific pathogens posing a risk in cirrhosis and availability of preventive strategies. RESULTS: Immunodeficiency in cirrhosis is multifactorial and might not be reversed by isolated interventions. Epidemiologic data on the incidence of specific infections and risk factors are scarce, only Child-Pugh stage C being a common denominator. A variety of common, such as Staphylococcus aureus, Streptococcus pneumoniae, and Mycobacterium tuberculosis, as well as uncommon pathogens possess significant risks in cirrhosis. Certain aspects of these risks remain though unrecognized. CONCLUSIONS: To better understand the overall burden of bacterial infections on cirrhotic patients' survival, more data on preventive efficacy of pneumococcal vaccination, on the overall burden of tuberculosis, and the relative incidence of specific infections as endocarditis are warranted.     

New antifungal agents

Treatment of fungal infections is an area of increasing concern. This is because of the complexity of underlying illness in affected patients as well as the limited number of antifungal agents available for use. Current strategies focus on prevention of these infections in patients at high risk; however, this has the potential to lead to the emergence of clinically resistant pathogens and superinfections in these patient populations. Future efforts need to focus on earlier diagnosis and more targeted prophylaxis strategies to limit unnecessary use of these potentially toxic pharmaceuticals. Of equal importance is the development of new therapeutic options that provide viable alternatives for practitioners as well as optimal administration of currently available agents. Recent work in this area has yielded a handful of new agents that provide the first step in improving efficacy in these severely immunosuppressed patients, but outcomes still remain suboptimal for many patients suffering from severe fungal infections and/or serious underlying diseases. Clinical antifungal drug resistance must be controlled by improving a series of antifungal therapeutic strategies.     

Pneumonia caused by herpesviruses in recipients of hematopoietic cell transplants

Viral pulmonary infections are a major cause of morbidity and mortality in recipients of hematopoietic cell transplantation. Members of the herpesviruses-cytomegalovirus, herpes simplex virus, varicella zoster virus, Epstein-Barr virus, as well as some of the more recently described herpesviruses such as HHV-6 and HHV-8-are frequently implicated in causing pulmonary infection in this population. Advances in diagnostic techniques and the use of preventive or preemptive therapies have altered the epidemiology of infections caused by some of the herpesviruses; however, these viruses continue to be a significant cause of morbidity and mortality in hematopoietic cell transplantation. This article provides an overview of pulmonary herpesvirus infections that occur after hematopoietic cell transplantation, with an emphasis on new developments in epidemiology, diagnosis, prophylaxis, and treatment.     

Ventricular Assist Device Infections

Ventricular Assist Devices(VAD) are the commonest form of cardiac mechanical support, used as bridge to transplantation but also as destination therapy in non-transplant-eligible patients in whom transplantation is considered unsuitable based on age criteria. Infections are common and can significantly impact on patient outcome. Strategies to prevent and treat infections have not been assessed by randomised controlled trials, a difficult task due to the multiplicity of devices and their ongoing evolution. This review summarises the recent literature on infections in VAD-supported patients, including the recently proposed definitions, microbiology, diagnosis, treatment and preventive strategies.     

Respiratory Viruses in Solid Organ Transplant Recipients

Solid organ transplantation is often lifesaving, but does carry an increased risk of infection. Respiratory viral infections are one of the most prevalent infections, and are a cause of significant morbidity and mortality, especially among lung transplant recipients. There is also data to suggest an association with acute rejection and chronic lung allograft dysfunction in lung transplant recipients. Respiratory viral infections can appear at any time post-transplant and are usually acquired in the community. All respiratory viral infections share similar clinical manifestations and are all currently diagnosed using nucleic acid testing. Influenza has good treatment options and prevention strategies, although these are hampered by resistance to neuraminidase inhibitors and lower vaccine immunogenicity in the transplant population. Other respiratory viruses, unfortunately, have limited treatments and preventive methods. This review summarizes the epidemiology, clinical manifestations, therapies and preventive measures for clinically significant RNA and DNA respiratory viruses, with the exception of SARS-CoV-2. This area is fast evolving and hopefully the coming decades will bring us new antivirals, immunologic treatments and vaccines.     

Nosocomial viral respiratory infections

Nosocomial infections with respiratory tract viruses, particularly influenza and respiratory syncytial viruses, account for the majority of serious nosocomial viral disease. Chronically ill, immunocompromised, elderly, and very young hosts are especially vulnerable to potentially life-threatening involvement of the lower respiratory tract. Effective preventive strategies are based upon early accurate viral diagnosis and an appreciation of the epidemiology and mechanisms of transmission for each viral agent. Influenza viruses spread via airborne dispersion of small particle aerosols, resulting in explosive outbreaks; control measures emphasize immunization and chemoprophylaxis of susceptible patients and personnel, and isolation of those already infected. Transmission of respiratory syncytial virus, in contrast, seems to require closer contact, with virus passed on hands, fomites, or in large droplets inoculated into the eyes and nose at close range. Strategies for control of nosocomial respiratory syncytial virus are designed to interrupt hand carriage and inoculation of virus onto mucous membranes.     

Viral infections in lung transplantation

Viral infections account for up to 30% of all infectious complications in lung transplant recipients, remaining a significant cause of morbidity and even mortality. Impact of viral infections is not only due to the direct effects of viral replication, but also to immunologically-mediated lung injury that may lead to acute rejection and chronic lung allograft dysfunction. This has particularly been seen in infections caused by herpesviruses and respiratory viruses. The implementation of universal preventive measures against cytomegalovirus (CMV) and influenza (by means of antiviral prophylaxis and vaccination, respectively) and administration of early antiviral treatment have reduced the burden of these diseases and potentially their role in affecting allograft outcomes. New antivirals against CMV for prophylaxis and for treatment of antiviral-resistant CMV infection are currently being evaluated in transplant recipients, and may continue to improve the management of CMV in lung transplant recipients. However, new therapeutic and preventive strategies are highly needed for other viruses such as respiratory syncytial virus (RSV) or parainfluenza virus (PIV), including new antivirals and vaccines. This is particularly important in the advent of the COVID-19 pandemic, for which several unanswered questions remain, in particular on the best antiviral and immunomodulatory regimen for decreasing mortality specifically in lung transplant recipients. In conclusion, the appropriate management of viral complications after transplantation remain an essential step to continue improving survival and quality of life of lung transplant recipients.     

How to manage IBD in patients with infections or malignancies?

Infections and malignancies are a major issue for clinicians in the management of patients with IBD because of concerns about the safety of drugs currently used in treatment, including immunosuppressive agents, steroids and tumor necrosis factor (TNF) antagonists. Infections are strongly associated with IBD both in their etiopathogenesis and in their clinical course. A number of viral infections, tuberculosis and other therapy-related infections create challenges for the successful management of intestinal disease with immunosuppressive agents or TNF antagonists. Recently published guidelines offer a strong support to deal with these issues. Major concern about IBD patients with malignancies is related to the consequences of chemotherapy on the intestinal disease, the risk of maintaining immunosuppressant or anti-TNF therapy after the diagnosis of malignancy and the management of a clinical relapse of IBD in patients with a recent diagnosis of malignancy. Further research is required to optimize strategies for IBD patients with malignancies. At the moment, all therapeutic choice is made on an individual basis, with an integrative multidisciplinary approach.     

Strategies to enhance immune function in hematopoietic transplantation recipients who have fungal infections

The challenges in the treatment of systemic fungal infections after HSCT include: (1) changing epidemiology as less drug-susceptible saprophytic fungi are increasingly associated with human disease; (2) the difficulty of early and correct diagnosis, even with the new generation of enzymatic immunoassays; (3) the inability to reduce or eliminate predisposing factors, especially severe immune suppression in most transplant patients with these infections and (4) the uncertain role of antifungal drug combinations and risk of drug antagonism complicating effective empiric-pre-emptive therapy. Current, developing and future immune enhancement strategies including recombinant granulocyte- and granulocyte macrophage-colony stimulating factor (GM-CSF), interferon-gamma (IFN-gamma), adjuvant pro-inflammatory cytokine therapy during mobilized donor granulocyte transfusions, therapeutic potential of pentraxin, adaptive immune transfer and dendritic cell fungal vaccines. Improved understanding of the molecular pathogenesis of fungal infections and of the complexity of host antifungal immune responses has provided the critical information to readdress existing treatment paradigms and further evaluate the role of GM-CSF and IFN-gamma early in the course of therapy against life-threatening fungal infections in high-risk patients following stem cell transplantation.     

Recent trends in the epidemiology of invasive mycoses

PURPOSE OF REVIEW: Invasive mycoses are emerging as an important public health problem. This development has occurred in large measure due to the increasing numbers of persons at risk. In addition, advances in therapeutic technologies and in particular the development of novel immunosuppressive therapies have prolonged the period of risk for many individuals. RECENT FINDINGS: Although rates of candida bloodstream infections have been increasing over the past several decades, recent evidence suggests this trend may be reversing. The emergence of non-albicans Candida species, and in particular C. glabrata, has been documented. Invasive aspergillosis and other mold infections have become a significant and increasing problem in hematopoietic stem cell transplant recipients and certain high-risk groups of solid organ transplant recipients. These infections are associated with high mortality rates. Despite marked reductions in the rates of AIDS-associated fungal infections in the USA and other developed countries, the burden of these mycoses in developing countries is large and increasing. SUMMARY: While gains have been made in the treatment and prevention of invasive mycoses, changes in the epidemiology of these infections and in healthcare practices have resulted in the emergence of new at-risk populations. A better understanding of specific risk factors will be needed if prevention strategies, such as chemoprophylaxis and environmental control measures, are to become more widely applicable and cost-effective.