Infectious Disorders - Drug Targets (Formerly Current Drug Targets - Infectious Disorders) - Volume 11, Issue 1, 2011

The fields of infectious diseases and hematology frequently intersect. Many hematologic disorders, particularly the hematologic malignancies, predispose the patient to a wide range of infectious complications. Conversely, infections have an effect on the hematologic picture, either directly, such as anemia of chronic infection, or leukocytosis associated with most bacterial infections, or indirectly, such as sepsis complicated by coagulopathy leading to disseminated intravascular coagulation (DIC). In this issue, we have chosen a series of articles written by authors with respective expertise in the study and clinical practice of either infectious diseases or hematology. These articles address the complexity of the pathogenesis and the clinical picture when the body is affected by both infection and hematologic disorders. We hope they will provide valuable information for the practitioner of both of these two disciplines. To begin with, Young, in her article entitled “Epidemiology and management of infectious complications of contemporary management of chronic leukemias,” provides a unique overview of the current management strategies for the control of chronic leukemias (chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia). She carefully reviews the mechanism of action and associated infections with the current treatment modalities, with monoclonal antibodies taking an increasing role. She then reviews the current literature correlating infectious risk with each of these treatments and provides evidence-based recommendations on prophylaxis strategies to minimize the impact of these complications. Next, Tessier and Sifri, in their article entitled “Epidemiology and Prevention of Bacterial Infections in Patients with Hematologic Malignancies,” provide a review focused on the pathogenesis for the increased risk of bacterial infections complications, along with epidemiology of bacterial infections in patients with hematologic malignancies and evidence-based recommendations on prevention and management of these complications. Hematopoietic stem cell transplantation is now an integral part of the management of malignant hematologic disorders. Infection is all too common a major cause of the morbidity and mortality of this procedure. Magauran and Salgado, in their article entitled “Challenges and Advances in Infection Control of Stem Cell Transplant Recipients,” review the current data to support infection control practices at stem cell transplant centers. The authors review the epidemiology of nosocomial infections in this unique population and provide evidence-based recommendations on how to mitigate these infections. In contrast to bacterial infection, virus presents another challenge in hematologic malignancies. Angarone, in his article entitled “Epidemiology and prevention of viral infections in patients with hematologic malignancies,” reviews the epidemiology and evidence-based prophylactic strategies to minimize viral complications of individuals with hematologic malignancies. Ison, in his article entitled “Epidemiology, prevention, and management of influenza in patients with hematologic malignancy,” provides a review of salient studies related to influenza infection in this unique population. Available data on the impact and management of the pandemic influenza A/H1N1 is also reviewed as are current guidelines for the prevention and management of seasonal and pandemic influenza infection. From the hematologic standpoint, anemia is often an important component of the clinical spectrum in infections. Kwaan detailed review in his article entitled “Infection and anemia the pathogenesis of changes in hematologic parameters directly or indirectly resulting from infections”. Specifically he reviews the conditions associated with anemia in patients with infections (anemia of chronic disease, hemolysis, red cell aplasia), hemolysis secondary to infection (parasitic destruction of erythrocytes, toxin-induced hemolysis, hemolytic-uremic syndrome, and hemolysis complicating antimicrobial therapy), and anemia resulting from blood loss (DIC, viral hemorrhagic fevers, and parasitic invasion of vascular walls).

This is a review of the epidemiology and management of infectious complications in contemporary management of chronic leukemias. Patients with chronic leukemias typically are affected by nuisance infections due to the underlying hematologic condition, particularly hypogammaglobulinemia in CLL patients. With active treatment, particularly those agents that cause defects in cell-mediated immunity, the incidence of opportunistic infections increases although endogenous bacterial, mycobacterial, and fungal infections also occur. Exogenous treatment with immunoglobulin and antimicrobial prophylaxis, particularly anti-Pneumocystis prophylaxis, may be indicated in select patients. Routine vaccinations should be maintained in these patients and vaccination early in the course of treatment may result in improve protection.

Bacterial infections are a serious complication of hematologic malignancies and the therapies used to treat them. Neutropenia can result from the malignancy itself or develop as a complication of chemotherapy and remains a major risk factor for the development of infections in these patients. In addition, the mechanical and chemotherapeutic interventions applied to patients with hematologic malignancies impose additional challenges to host defenses against bacterial invasion. The bacteria responsible for most infections in this patient population have continued to evolve as different therapeutic, preventive, and preemptive strategies are introduced into the armamentarium for leukemias, lymphomas, and myelomas. Both Gram-negative and Gram-positive pathogens have become increasingly resistant to available antimicrobial agents, in part due to the increasing use of agents, especially the fluoroquinolones, to prevent bacterial infections. This review addresses recent clinical developments in the epidemiology and prevention of bacterial infections in these unique populations of patients.

Hematopoietic Stem Cell Transplantation (HSCT) has revolutionized the outcome of many malignant and nonmalignant disorders; however, infection still accounts for a substantial number of deaths after both allogeneic and autologous transplants. Hospital-acquired infections (HAI) such as bloodstream infections, pneumonias, and diarrhea are common in this population and account for significant morbidity and cost of care. Also, there is renewed focus on epidemiologically important organisms as the cause of HAI, most notably methicillin-resistant Staphylococcus aureus, vancomycin- resistant Enterococcus, multi-drug resistant gram-negative bacilli, and Clostridium difficile. We review the infectious risks of HSCT, including those due to HAI as well as measures to decrease these infectious complications. This includes discussion of measures to implement prior to transplant and measures to implement during the pre-engraftment phase, post-engraftment phase, and late phase after transplantation. Additionally, general infection control measures related to healthcare worker behavior as well as environmental control are reviewed. Despite the marked advances in the field of HSCT, challenges remain for clinicians and researchers to conduct properly designed studies to better describe the epidemiology of, risks for, and measures for prevention of transplant related infections.

Viral infections are some of the most frequent complications in patients with hematologic malignancies are viral infections. Infections caused by cytomegalovirus, herpes simplex virus, varicella zoster virus, hepatitis B virus and influenza virus are associated with high morbidity and mortality in this vulnerable population. Fortunately, a growing number of antiviral medications and vaccines are allowing for more effective prophylaxis against these pathogens. This article reviews the epidemiology and prophylactic strategies available for these opportunistic viral pathogens.

Influenza results in annual epidemics of respiratory viral illness during the winter; when a novel virus enters the human population, a pandemic may result with a larger proportion of the population sickened. Unlike the mild and typically self-limited disease seen in immunocompetent patients, immunocompromised patients frequently have a more severe course. These individuals shed virus for a prolonged period of time, have a high rate of viral pneumonia, more frequently develop bacterial and fungal super-infections, and may develop late-onset airflow obstruction. Further, antiviral resistance develops more frequently in immunosuppressed patients. Although the cornerstone of prevention of influenza is vaccination, vaccine efficacy in patients with hematologic malignancies, particularly stem cell transplant recipients, is poor. Alternative preventative measures, such as seasonal antiviral prophylaxis can be considered. Lastly, there have been no prospective studies of antivirals in the management of influenza infections in these patients. As such, the optimal regimen and duration remains to be defined. Available evidence suggests that prolonged course are frequently needed. Patients who fail to response or have relapsed infections should be tested for emergence of antiviral resistance and alternative diagnoses should be investigated.

Anemia most frequently accompanies infection in varying degrees and in different forms. Anemia of inflammation is the most common and is due to over-expression of hepcidin. This is followed by hemolytic anemia, red cell aplasia and blood loss. The degree of anemia may not necessarily be proportional to the severity of the infection, nor is it specific for the type of infection. A clear understanding of these diverse causes and a recognition that they often occur in combination can be of enormous assistance in forming a proper diagnosis and an appropriate management plan.

The use of blood donor history and state-of-the-art FDA-licensed serological and nucleic acid testing (NAT) assays have greatly reduced the “infectious window” for several transfusion-transmitted pathogens. Currently transmission of human immunodeficiency virus (HIV), Human T-cell Lymphotropic Virus (HTLV), hepatitis viruses and West Nile Virus are rare events. The seroprevalence of cytomegalovirus in the donor population is high and cytomegalovirus infection can cause significant complications for immunocompromised recipients of blood transfusion. Careful use of CMV seronegative blood resources and leukoreduction of blood products are able to prevent most CMV infections in these patients. Currently, bacterial contamination of platelet concentrates is the greatest remaining infectious disease risk in blood transfusion. Specialized donor collection procedures reduce the risk of bacterial contamination of blood products; blood culture and surrogate testing procedures are used to detect potential bacterially contaminated platelet products prior to transfusion. A rapid quantitative immunoassay is now available to test for the presence of lipotechoic acid and lipopolysaccharide bacterial products prior to platelet transfusion. Attention has now turned to emerging infectious diseases including variant Creutzfeldt-Jakob disease, dengue, babesiosis, Chagas' disease and malaria. Challenges are presented to identify and prevent transmission of these agents. Several methods are being used or in development to reduce infectivity of blood products, including solvent-detergent processing of plasma and nucleic acid cross-linking via photochemical reactions with methylene blue, riboflavin, psoralen and alkylating agents. Several opportunities exist to further improve blood safety through advances in infectious disease screening and pathogen inactivation methods.

Tat is a regulatory viral protein known as transactivator of HIV-1 genes but Tat is also secreted in the blood from HIV-1 infected cells. Extra cellular Tat can cross cellular membranes to trigger apoptosis and might explain the incapacity of the cellular immunity to eliminate HIV-1 infected cells. There is a controversy regarding Tat structure with studies suggesting that Tat would be a naturally unfolded protein. Here, we show that synthetic Tat variants need to be folded to have a transactivation activity in a cellular assay but this folding is unstable regarding the buffers and/or pH used as solvent. We show also that the recognition of a Tat variant versus peptides, covering its sequence, was different. Using an indirect ELISA method with 40 sera from volunteer HIV-1 infected patients, we show that Tat was recognized by 19 human sera either exclusively (n=8) or with Tat peptides (n=11). Dot Blot showed that unfolded Tat was no longer detectable by sera of the first group (n=8) compared to folded Tat. As a conclusion, this study suggests that Tat could be a naturally folded protein in the blood of HIV infected patients.

Computational chemistry has always played a key role in anti-viral drug development. The challenges and the quickly rising public interest when a virus is becoming a threat has significantly influenced computational drug discovery. The most obvious example is anti-AIDS research, where HIV protease and reverse transcriptase have triggered enormous efforts in developing and improving computational methods. Methods applied to anti-viral research include (i) ligandbased approaches that rely on known active compounds to extrapolate biological activity, such as machine learning techniques or classical QSAR, (ii) structure-based methods that rely on an experimentally determined 3D structure of the targets, such as molecular docking or molecular dynamics, and (iii) universal approaches that can be applied in a structure- or ligand-based way, such as 3D QSAR or 3D pharmacophore elucidation. In this review we summarize these molecular modeling approaches as they were applied to fight anti-viral diseases and highlight their importance for anti-viral research. We discuss the role of computational chemistry in the development of small molecules as agents against HIV integrase, HIV-1 protease, HIV-1 reverse transcriptase, the influenza virus M2 channel protein, influenza virus neuraminidase, the SARS coronavirus main proteinase and spike protein, thymidine kinases of herpes viruses, hepatitis C virus proteins and other flaviviruses as well as human rhinovirus coat protein and proteases, and other picornaviridae. We highlight how computational approaches have helped in discovering anti-viral activities of natural products and give an overview on polypharmacology approaches that help to optimize drugs against several viruses or help to optimize the metabolic profile of and anti-viral drug.

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