Immunopharmacotherapy of non-infectious uveitis: where do we stand?

With ever-evolving concept of personalised medicine backed up with specific biomarkers for ocular inflammatory disease, there is a sudden surge of using biologics in non-infectious recalcitrant posterior uveitis. Have we understood these biologic agents enough to embark on this long enduring journey with the patient to optimise control of intraocular inflammation? On the other hand, there is still a strong inhibition of using these novel agents in management of uveitis even at tertiary referral centres. Immunopharmacotherapy of non-infectious uveitis poses a significant conundrum for both physicians and patients as it is like a two-edged sword effective to control inflammation but at the same time potentially toxic, suspected of causing long-term adverse effects. Systemic immunosuppressive therapy is used in a substantial number of most vision-threatening ocular inflammatory diseases. There is lack of randomised control trials establishing the safety of this therapy and our current practice pattern is based on retrospective studies and personal experience in using this treatment modality. This overview will highlight on the current dilemma faced by the clinicians in opting for steroid-sparing immunosuppressive therapy.     

Gastric tonometry: where do we stand?

Gastric tonometry has proved to be a sensitive but not specific predictor of outcome in the critically ill. The data accumulated to date indicate that those patients able to achieve or maintain a normal gastric mucosal pH do better than those who do not. In addition, therapy aimed at improving an abnormal gastric mucosal pH has proved to be less successful. These findings may simply indicate that tonometry identifies those "responders" and "nonresponders," as becomes increasingly apparent in populations of critical care patients receiving interventional therapy. Gastric tonometry has undergone a number of methodologic changes over the last decade, seeing a switch from saline to automated gas tonometry. Along with this switch of methodology has come a deeper scrutiny of the indices used to assess gut perfusion. Most studies (including all the interventional ones) have used gastric mucosal pH. The newer indices of gut luminal PCO2 (PgCO2) referenced to arterial CO2 (PgCO2-PaCO2) or end tidal CO2 (PgCO2-PeCO2), although relatively well validated, remain to be proven as predictors of outcome or guides to interventional therapy. If we take a fresh look at the interventional trials in intensive care patients, there is a very definite trend toward benefit in the protocol groups, although they are generally reported as negative studies. There is much to be accomplished, however, before we accept the gastric tonometer as a routine tool with which to guide therapy based on gastrointestinal perfusion, including a greater understanding of gastrointestinal physiology and, as ever, the call for an adequately powered prospective randomized controlled trial to evaluate the clinical utility of gas tonometry.     

Immunotherapy and immunoprevention of cancer: where do we stand?

Although evolution has shaped the immune system to control microbial invasions, this does not necessarily mean that the immune system can not be triggered to eliminate tumour cells. The exploitation of the terrific potential of the immune system to recognise cell alterations and to selectively destroy large populations of neoplastic cells is a possibility made even more attractive by the advances in our understanding of the immune mechanisms and our ability to manipulate them. This review summarises the state of the different immunotherapy strategies available or in development today, and examines the future developments that hold out the promise of an effective control of cancer growth.     

Reviewing the use of ventricular assist devices in the elderly: where do we stand today?

Introduction: Implantation of left ventricular assist devices (LVADS) in older patients appears to be an attractive option in the wake of donor shortage and increasing incidence and prevalence of end stage heart failure. Since the inception of the artificial heart program half a century ago tremendous progress in research and development has led to utilization of more sophisticated devices. VADs have therefore emerged as a successful therapy for extending life with meaningful quality.

Areas covered: This review will address the use of LVADS as a bridge to transplantation, destination therapy and comparison of LVAD therapy with alternate list heart transplantation in the elderly population.

Expert commentary: Age >70 years is an important aspect when assessing LVAD risk, but other characteristics appear to be better predictors of LVAD survival. Elevated pre-operative creatinine, bilirubin and ischemic etiology predispose to a higher risk of mortality. Creatinine has been shown to be a very powerful predictor in post LVAD survival. Based on the existing literature, the authors suggest an algorithm which could be useful when evaluating patients for LVAD implantation.     

Ethical aspects of cardiopulmonary resuscitation in premature neonates: where do we stand?

Advances in diagnosis, techniques, therapeutic interventions, organisation of perinatal care, and socio-economic factors have all contributed to the survival after resuscitation and intensive care of neonates with extremely low birth weight and gestational age. While morbidity during the first years of life in those infants does not increase, at school age multiple dysfunctions may become apparent. What are the limits of intensive care for the newborn? Is it right to use extreme technical and economic measures for neonates with a borderline chance of survival? What is justifiable for the neonate, the family, the society and how does legislation interfere in a decision process which involves starting, stopping or continuing intensive care? A short historical overview for the care of the newborn is given, followed by the outcome after resuscitation and treatment of the very low birth weight infant. Published management strategies and recommendations are discussed.     

Bioinformatical assistance of selecting anti-HIV therapies: where do we stand?

In this opinion statement, we give a critical synopsis of the state-of-the-art of bioinformatic HIV resistance analysis and point out what we consider to be challenges and perspectives.     

Endovascular repair of abdominal aortic aneurysms: where do we stand?

Endovascular repair of abdominal aortic aneurysms has evolved dramatically within the past few years. In light of the potential to reduce morbidity and mortality associated with open surgical repair, endoluminal grafting offers therapeutic options to patients who are not surgical candidates because of comorbidities. With the development of bifurcated devices, more complex aneurysms may be treated by endovascular grafting. Although successful placement of endovascular grafts requires a pronounced learning curve, including appropriate patient selection, midterm results seem consistent with those of traditional open repair of aneurysms. This review describes the current indications, minimal requirements, different devices and associated techniques, and potential complications of endoluminal repair of abdominal aortic aneurysms. Future aspects of endoluminal grafting are also discussed.     

Uterus transplantation: where do we stand today and where should we go?

If transplantation of the uterus is developed into a safe method with a reasonable chance for the patient to carry an uneventful pregnancy, this procedure could become a feasible fertility treatment for women with absolute uterus factor infertility. The activity in this research field is growing and during the past 5 years several reports have been published. In this brief review the authors summarize the state of research in this field and also speculate on what might lie ahead.     

HIV and malaria interactions: where do we stand?

Reversing the spread of HIV infection and the incidence of malaria constitute two of the Millenium Development Goals. However, despite recent achievements, both diseases still entail global heath problems. Furthermore, their overlapping geographical distribution raises concerns and challenges for potential immunological, clinical and therapeutic interactions. It has been reported that HIV infection increases malaria susceptibility and reduces the efficacy of antimalarial drugs. On the other hand, the effect of malaria on HIV-infected individuals has also been explored, with the parasitic infection increasing the risk of HIV disease progression and mother-to-child transmission of HIV. The spread of malaria and parasite resistance to antimalarials could also be accelerated by HIV-associated immunosuppresion. Current knowledge of the epidemiological, clinical, immunological and therapeutic interactions of the two diseases is reviewed in this article. We focus on the latest available data, pointing out key future research areas and challenges of the field.     

Clinical review: Clinical imaging of the sublingual microcirculation in the critically ill - where do we stand?

ABSTRACT: A growing body of evidence exists associating depressed microcirculatory function and morbidity and mortality in a wide array of clinical scenarios. It has been suggested that volume replacement therapy using fluids and/or blood in combination with vasoactive agents to modulate macro- and microvascular perfusion might be essential for resuscitation of severely septic patients. Even after interventions effectively optimizing macrocirculatory hemodynamics, however, high mortality rates still persist in critically ill and especially in septic patients. Therefore, rather than limiting therapy to macrocirculatory targets alone, microcirculatory targets could be incorporated to potentially reduce mortality rates in these critically ill patients. In the present review we first provide a brief history of clinical imaging of the microcirculation and describe how microcirculatory imaging has been of prognostic value in intensive care patients. We then give an overview of therapies potentially improving the microcirculation in critically ill patients and propose a clinical trial aimed at demonstrating that therapy targeting improvement of the microcirculation results in improved organ function in patients with severe sepsis and septic shock. We end with some recent technological advances in clinical microcirculatory image acquisition and analysis.     

Fluconazole for the management of invasive candidiasis: where do we stand after 15 years?

Candida spp. are responsible for most of the fungal infections in humans. Available since 1990, fluconazole is well established as a leading drug in the setting of prevention and treatment of mucosal and invasive candidiasis. Fluconazole displays predictable pharmacokinetics and an excellent tolerance profile in all groups, including the elderly and children. Fluconazole is a fungistatic drug against yeasts and lacks activity against moulds. Candida krusei is intrinsically resistant to fluconazole, and other species, notably Candida glabrata, often manifest reduced susceptibility. Emergence of azole-resistant strains as well as discovery of new antifungal drugs (new triazoles and echinocandins) have raised important questions about its use as a first line drug. The aim of this review is to summarize the main available data on the position of fluconazole in the prophylaxis or curative treatment of invasive Candida spp. infections. Fluconazole is still a major drug for antifungal prophylaxis in the setting of transplantation (solid organ and bone marrow), intensive care unit, and in neutropenic patients. Prophylactic fluconazole still has a place in HIV-positive patients in viro-immunological failure with recurrent mucosal candidiasis. Fluconazole can be used in adult neutropenic patients with systemic candidiasis, as long as the species identified is a priori susceptible. Among non-neutropenic patients with candidaemia fluconazole is one of the first line drugs for susceptible species. Cases reports and uncontrolled studies have also reported its efficacy in the setting of osteoarthritis, endophthalmitis, meningitis, endocarditis and peritonitis caused by Candida spp. among immunocompetent adults. In paediatrics, fluconazole is a well tolerated and major prophylactic drug for high-risk neonates, as well as an alternative treatment for neonatal candidiasis. Importantly 15 years after its introduction in the antifungal armamentarium, fluconazole is still a first line treatment option in several cases of invasive candidiasis. Its prophylactic use should however be limited to selected high-risk patients to limit the risk of emergence of azole-resistant strains.