Viral Infections In Immunocompromised Patients Research Articles

Interaction of Adenovirus E1A with the HHV8 Promoter of Latent Genes: E1A Proteins are Able to Activate the HHV-8 LANAp in MV3 Reporter Cells

Human herpesvirus 8 (HHV-8) is associated with Kaposi’s sarcoma, body cavity-based lymphoma, and Castleman’s disease. Adenoviral (Ad) E1A proteins regulate the activity of cellular and viral promoters/enhancers and transcription factors and can suppress tumorigenicity of human cancers. As (i) HHV-8 and Ad may co-exist in immunocompromised patients and (ii) E1A might be considered as therapeutic transgene for HHV-8-associated neoplasms we investigated whether the promoter of the latency-associated nuclear antigen (LANAp) controlling expression of vCyclin, vFLIP, and LANA proteins required for latent type infection is regulated by E1A. Transfection experiments in MV3 melanoma cells revealed activation of the LANAp by Ad5 E1A constructs containing an intact N terminus (aa 1-119). In particular, an Ad12 E1A mutant, Spm2, lacking six consecutive alanine residues in the “spacer” region activated the HHV-8 promoter about 15-fold compared to vector controls. In summary, we report the activation of the LANAp by E1A as a novel interaction of E1A with a viral promoter. These data may have relevance for the management of viral infections in immunocompromised patients. A role for E1A as a therapeutic in this context remains to be defined.

Respiratory Syncytial Virus Infection in Immunocompromised Patients Revisited

Respiratory Syncytial Virus Infection in Immunocompromised Patients Revisited

Optimizing Culture Conditions for Ex Vivo Expansion of Virus Specific T Cells.

Adoptive immunotherapy with virus specific CD8+ cytotoxic T lymphocytes (CTL) is currently an option for treatment of viral infections after allogeneic stem cell transplantation. A major obstacle for clinical grade production of virus specific CTL is to retain the antigen specific clones, which can be easily deleted during ex vivo expansion. Manipulation of CD3/CD28 engagement, depletion of T regulatory (Treg) cells before expansion and prestimulation with antigen presenting cells were explored in this study. Mononuclear cells were obtained from HLA-A2+ donors by leucapheresis. Lymphocytes were enriched by elutriation, stimulated with anti-CD3/anti-CD28high Dynabeads or Dynabeads® ClinExVivo™ CD3/CD28 and cultured for 10 days in CellGro media supplemented with human AB serum and IL-2. Virus specific CD8+ CTL were quantified by flow using pentamer staining. By using anti-CD3/ anti-CD28high Dynabeads a more balanced expansion of CD4+ and CD8+ subsets was obtained, while Dynabeads ClinExVivo CD3/CD28 allowed a higher expansion of CD8+ subset and therefore a higher expansion of the virus specific CTL. A high Dynabead: T cell ratio (3:1) deleted completely the virus specific CTL. By reducing this ratio we could retain the virus specific CTL after expansion. No benefits were observed by adding extra Dynabeads during expansion. It is known that Treg cells can inhibit expansion of all T cell subsets. By depleting Treg cells with CD25 Dynabeads prior to T cell expansion, we observed a significantly increased expansion of all T cells, including virus specific CTL. In some patients low numbers of virus specific CTL can be detected. To increase the numbers of antigen specific CTL we have included a prestimulation step using peptide-loaded mononuclear cells prior to expansion with Dynabeads, which gave more than 3000- fold expansion of virus specific CTL. We are currently exploring the phenotype profile of expanded CTL (CD62L, CCR7, CD57, CD27, CD28 and CTLA-4), functionality (cytokine secretion and proliferative capacity) and cytotoxicity. This protocol can be upgraded to clinical grade production of virus specific CTL for treatment of viral infections in immunocompromised patients.

Advanced therapeutic and prophylactic strategies for Epstein–Barr virus infection in immunocompromised patients

Epstein–Barr virus (EBV) is an ubiquitous human herpesvirus. Primary infection is generally subclinical but in certain circumstances, such as in patients with either hereditary or secondary immunodeficiency, EBV infection may cause overt disease that is often lethal. Strategies for the prophylaxis and treatment of these potentially life-threatening complications of EBV infection have advanced dramatically. They include immunological-based approaches targeted at EBV-infected cells, as well as improvement in the treatment of the underlying and predisposing disease. This review will discuss EBV biology and immune events that occur in both immunocompetent and immunocompromised individuals and introduce the novel prophylactic and therapeutic strategies for EBV-associated life-threatening diseases.

Community Respiratory Virus Infections in Immunocompromised Patients: Hematopoietic Stem Cell and Solid Organ Transplant Recipients, and Individuals with Human Immunodeficiency Virus Infection

Infection is the leading cause of morbidity and mortality in immunocompromised patients such as hematopoietic/solid organ transplant recipients and individuals with human immunodeficiency virus. Community respiratory virus infections are increasingly recognized as a significant threat to these patients. This article reviews current information in the clinical field of community respiratory viruses, including several newly discovered respiratory viruses. Respiratory syncytial virus, influenza viruses, parainfluenza viruses, and adenoviruses cause the most serious disease in immunocompromised hosts, but other respiratory viruses are becoming increasingly appreciated as a cause of both upper and lower respiratory tract disease. The clinical impact of these new viruses, including human metapneumovirus, non-SARS human coronaviruses, and human bocavirus, is not yet clear. Modern molecular technology has made the discovery of new viruses possible; the use of these new technologies in direct patient care is not yet standard but is becoming increasingly utilized. Clinicians should appreciate the potential for the development of antiviral resistance to influenza antivirals in immunocompromised patients.

Update on viral infections in immunocompromised patients

Viral infections are one of the most frequent complications of oncohematologic and transplanted patients. Here we review some of the most interesting clinical publications of 2004 and 2005. A brief introduction of each virus or issue is given followed by a discussion of the related publications. In relation to CMV we reviewed: 1) the recommendations of the European Group for Blood and Marrow Transplantation for CMV management in stem-cell hematopoietic transplants (HSCT); 2) a meta-analysis that evaluated the efficacy of different strategies for the prevention of CMV in solid organ transplants; 3) the impact of CMV disease before HSCT in the outcome of the transplants. A recent publication found a relation between herpesvirus 6 infection and increased mortality. This is a novel finding, not previously described, that reinforces the importance of the so-called “indirect effects” of the beta-herpesvirus. In the largest study performed until now of influenza in HSCT recipients, early antiviral therapy with oseltamivir was more effective than rimantadine for both preventing progression from influenza-A upper respiratory infection to pneumonia and reducing influenza-A pneumonia mortality. The human metapneumovirus (hMPV) is a newly described virus identified in 2001. The epidemiological and clinical characteristics of hMPV respiratory infections were described in a large group of oncohematologic patients. A novel approach was published for the treatment of HLTV-1 infections based on the pathogenesis of this infection. Finally, an exciting paper from the Perugia group showed that cloning of pathogen-specific T-cells seems a promising approach in the management of certain infections after HSCT.

Viral Infections in Immunocompromised Patients

Viral Infections in Immunocompromised Patients

Community-acquired respiratory viruses

Community-acquired respiratory viruses

Viral infections in immunocompromised patients: what's new with respiratory viruses?

The leading cause of death in solid organ and hematopoietic stem cell transplant recipients is infection. The respiratory viruses, particularly respiratory syncytial virus, influenza, parainfluenza, adenovirus, and picornaviruses, are increasingly recognized as significant pathogens in these populations. Respiratory syncytial virus has again been found to be the most common of the respiratory viruses causing severe infections in transplant recipients. Advances in prevention, particularly with regard to infection control practices, and to lesser extent treatment have had a substantial impact on the frequency and outcomes of this infection. New studies have clarified the impact of influenza in the hematopoietic stem cell transplant recipients and have provided evidence to support the use of M2 and neuraminidase inhibitors for early treatment. The epidemiology of parainfluenza and adenovirus in transplant recipients has been clarified, although therapeutic modalities are still limited and understudied. New antiviral medications may bring improved outcomes of picornavirus infections in this population. Finally, a new virus, the human metapneumovirus, has recently been described and may be a significant respiratory pathogen in immunocompromised transplant recipients. Studies published over the past year have documented a new respiratory pathogen. They have also resulted in improved understanding of the epidemiology of all of the respiratory virus pathogens, and have contributed to improve management of respiratory syncytial virus and influenza infection in hematopoietic stem cell transplant and solid organ transplant recipients.

Evaluation of the Prodesse Hexaplex Multiplex PCR Assay for Direct Detection of Seven Respiratory Viruses in Clinical Specimens

We evaluated the Hexaplex assay (Prodesse, Waukesha, WI) for the detection of 7 respiratory viruses (influenza A and B, parainfluenza 1-3, and respiratory syncytial virus [RSV] A and B). The Hexaplex assay was performed on 300 respiratory samples during the 1999-2000 respiratory virus season. Results of this assay were compared with shell vial cell culture and/or direct fluorescent antibody stain. The overall sensitivity and specificity of the assay were 96.6% and 94.1%, respectively. The respective sensitivity and specificity of the Hexaplex assay for detection of specific virus groups were as follows: influenza A, 98.6% and 97.8%; influenza B, 100% and 100%; and for parainfluenza viruses (1-3), 100% and 99.1%. The assay did not perform as well with patients infected with RSV: sensitivity and specificity were 91.0% and 98.6%, respectively. There are 2 major drawbacks to this assay: it is technically demanding (3-4 hours hands-on time), and it is expensive ($80-$90 direct cost). Nevertheless, because of the excellent sensitivity and specificity, the Hexaplex assay may be valuable in the diagnosis of respiratory viral infections in immunocompromised patients.

Herpesvirus-Induced Diseases: Oral Manifestations and Current Treatment Options

The dentist is often the first health professional to be contracted by patients who develop acute orofacial symptoms of viral conditions such as shingles (varicella zoster) or herpetic gingivostomatitis. The diagnosis, treatment, and management of virally induced oral diseases is a challenge inasmuch as their presentation is atypical and may be complicated by immunosuppression. However, an increasing body of knowledge regarding the manifestations of viral infections in immunocompromised patients and the advances achieved in antiviral drug therapy during the past several years should make the task less daunting for the dentist. In this paper, the natural history, typical and atypical oral manifestations, diagnosis, current treatment options, and advances in the prevention of common herpesvirus-induced diseases are reviewed, with particular attention to primary and recurrent varicella zoster virus and herpes simplex type 1 infections.

Passive Immunity in Prevention and Treatment of Infectious Diseases

Antibodies have been used for over a century in the prevention and treatment of infectious disease. They are used most commonly for the prevention of measles, hepatitis A, hepatitis B, tetanus, varicella, rabies, and vaccinia. Although their use in the treatment of bacterial infection has largely been supplanted by antibiotics, antibodies remain a critical component of the treatment of diptheria, tetanus, and botulism. High-dose intravenous immunoglobulin can be used to treat certain viral infections in immunocompromised patients (e.g., cytomegalovirus, parvovirus B19, and enterovirus infections). Antibodies may also be of value in toxic shock syndrome, Ebola virus, and refractory staphylococcal infections. Palivizumab, the first monoclonal antibody licensed (in 1998) for an infectious disease, can prevent respiratory syncytial virus infection in high-risk infants. The development and use of additional monoclonal antibodies to key epitopes of microbial pathogens may further define protective humoral responses and lead to new approaches for the prevention and treatment of infectious diseases.

Passive immunity in prevention and treatment of infectious diseases.

Antibodies have been used for over a century in the prevention and treatment of infectious disease. They are used most commonly for the prevention of measles, hepatitis A, hepatitis B, tetanus, varicella, rabies, and vaccinia. Although their use in the treatment of bacterial infection has largely been supplanted by antibiotics, antibodies remain a critical component of the treatment of diptheria, tetanus, and botulism. High-dose intravenous immunoglobulin can be used to treat certain viral infections in immunocompromised patients (e.g., cytomegalovirus, parvovirus B19, and enterovirus infections). Antibodies may also be of value in toxic shock syndrome, Ebola virus, and refractory staphylococcal infections. Palivizumab, the first monoclonal antibody licensed (in 1998) for an infectious disease, can prevent respiratory syncytial virus infection in high-risk infants. The development and use of additional monoclonal antibodies to key epitopes of microbial pathogens may further define protective humoral responses and lead to new approaches for the prevention and treatment of infectious diseases.

Infection Control of Nosocomial Respiratory Viral Disease in the Immunocompromised Host

Among immunocompromised adults, such as bone marrow transplant recipients, more than half of respiratory viral infections are complicated by pneumonia, with an associated mortality rate >50%. Nosocomial transmission of respiratory viral pathogens, such as respiratory syncytial virus (RSV) and influenza, in the immunocompromised patient has been reported frequently and usually occurs during a community outbreak. In view of the poor outcome in this subset of patients, intensive efforts should be directed at instituting prevention measures that would interrupt nosocomial transmission. At M.D. Anderson Cancer Center, a multifaceted infection control strategy resulted in a significant decrease in and almost complete interruption of the nosocomial transmission of RSV infections in immunocompromised patients over a 3-year period (1994–1996). For influenza virus, special emphasis should be given to vaccination of hospital personnel before the influenza season to prevent and control nosocomial transmission. In highly immunocompromised patients, prophylactic use of antiviral agents should be considered during an outbreak or when the frequency of nosocomial transmission is high. An aggressive multifaceted infection control strategy appears to be effective in reducing the frequency of nosocomial transmission of respiratory viral infections in immunocompromised patients. Universal and timely influenza vaccination of hospital personnel who care for immunocompromised patients is necessary.

Community Respiratory Virus Infections in Immunocompromised Patients with Cancer

Community respiratory viruses, such as respiratory syncytial virus (RSV), influenza viruses, parainfluenza viruses, adenoviruses, and picornaviruses, are an important cause of respiratory disease in the immunocompromised adult with cancer. Recent studies have demonstrated that a minimum of 31% of adult bone marrow transplant (BMT) recipients and 18% of adults with leukemia who are hospitalized with an acute respiratory illness have a community respiratory virus infection. The temporal occurrence of these infections in immunocompromised patients tends to mirror their occurrence in the community. The clinical illnesses range from self-limited upper respiratory illnesses to fatal pneumonias, depending on the type of virus and the type and degree of immunosuppression. The pneumonias may be viral, bacterial/fungal, or mixed. The highest frequency of progression to fatal viral pneumonia has been reported for RSV infections in recently transplanted BMT recipients and myelosuppressed patients with leukemia. Studies have suggested that early therapy for RSV pneumonia with a combination of aerosolized ribavirin and intravenous immunoglobulin may be of benefit. Defining effective prophylactic and therapeutic strategies will be a challenge, given the diversity of viruses, the wide spectrum of immunocompromised patients with varying vulnerability to serious community respiratory virus disease, and the frequent presence of other opportunistic infections and medical problems. A combination of antiviral drugs and immunotherapy may need to be considered for their potential additive effect as well as to prevent the emergence of resistant virus, as occurs during monotherapy for influenza with amantadine or rimantadine. The optimal therapies need to be defined in controlled trials; however, it appears that a favorable response will hinge on the initiation of therapy at an early stage of the respiratory illness.

Valacyclovir.

To discuss the clinical pharmacology, antiviral activity, clinical efficacy, and other therapeutic issues associated with valacyclovir use for the treatment of herpesvirus infections. Literature searches using MEDLINE were prospectively designed to include relevant articles and abstracts between January 1982 and March 1996. The searches focused on valacyclovir pharmacology, clinical efficacy, and issues associated with herpesvirus infections. Selection of clinical and basic science studies were limited to those focusing on valacyclovir. All articles with pertinent information relevant to the scope of this article were reviewed. Valacyclovir is an amino acid ester prodrug of acyclovir. It is currently approved for the treatment of herpes zoster infections in immunocompetent adults (1 g p.o. tid for 7 d) and recurrent episodes of genital herpes in immunocompetent adults (500 mg bid for 5 d). Valacyclovir is rapidly and almost completely hydrolyzed to acyclovir prior to systemic exposure. The bioavailability of valacyclovir is 54% compared to approximately 20% for oral acyclovir. At higher dosages (2 g qid), the plasma AUC of acyclovir following oral valacyclovir administration approximates that seen after intravenous administration of 10 mg/kg every 8 hours. Clinical data indicate that valacyclovir is at least as effective as acyclovir in decreasing the duration of pain associated with postherpetic neuralgia, and in reducing time to genital lesion healing and the length of the episode. Valacyclovir has improved bioavailability over acyclovir and is at least as efficacious. The favorable safety profile of acyclovir and increased systemic exposure make it a particularly ideal candidate for further studies of herpes group viral infections in immunocompromised patients.

173 Use of viral blood cultures in diagnosing herpes simplex virus infection in immunocompromised patients: S.F. Reising and L.R. Stanberry, Children's Hospital Research Foundation, University of Cincinnati, Cincinnati, OH, USA

173 Use of viral blood cultures in diagnosing herpes simplex virus infection in immunocompromised patients: S.F. Reising and L.R. Stanberry, Children's Hospital Research Foundation, University of Cincinnati, Cincinnati, OH, USA

Correlation of Viral Infection, Histology, and Mortality in Immunocompromised Patients with Pneumonia

The purpose of this study was to determine the occurrence and histologic correlates of viral infections in immunocompromised patients with pneumonia. Of the 44 immunocompromised patients studied, 37 had AIDS. Lung tissue from these patients, including 34 with pneumocystis pneumonia, was evaluated by in situ hybridization for the presence of cytomegalovirus (CMV), adenovirus, Epstein-Barr virus, and herpes simplex virus. Fifteen of the 44 patients were positive for at least one virus (34%); CMV (13 cases) was the most common. In an additional seven cases, CMV DNA was detected using the polymerase chain reaction (PCR), for an overall viral detection rate of 22 of 44 (50%). Histologic features were diagnostic of a viral infection in nine of 15 cases (60%) of the in situ positive cases and in nine of 22 (41%) of the tissues where viral DNA was detected by PCR. Mortality rate was significantly correlated with viral detection: 77% for the viral-positive cases and 27% for the viral-negative cases (p < 0.05). We concluded that in immunocompromised patients with pneumonitis, the detection of viral DNA is strongly correlated with survival and that histologic features of the inflamed lung tissue are a specific but insensitive means of diagnosing viral presence.

Herpes virus infections in immunocompromised patients: problems and therapeutic interventions.

Herpes virus infections are responsible for morbidity and mortality among immunosuppressed patients. During the last decade substantial advances have been achieved through improvement of diagnostic techniques, development of effective antiviral agents and the use of different strategies for prophylaxis and treatment. Cytomegalovirus infection and disease can today be prevented and treated effectively; however, antiviral resistance is beginning to emerge as a potential major clinical problem. Similarly, infections with herpes simplex virus and varicella-zoster virus can be effectively treated, but antiviral resistance has also emerged for these viruses. Two new herpes viruses, human herpes viruses 6 and 7, have been discovered, and it is possible that these viruses can also cause significant problems in immunosuppressed individuals. New antiviral agents will be needed during the next decade to allow further advances in the treatment of herpes virus infections.

Varicella-zoster virus infection in immunocompromised patients

The prophylactic effect of acyclovir (ACV) on varicella-zoster virus (VZV) infection in leukaemia patients who have undergone bone marrow transplantation (BMT) was reviewed. The benefits of the use of the laminar air flow (LAF) room in the prevention of nosocomial VZV infections in the haematological ward are also discussed. Since 1986 ACV has been administered to BMT patients to prevent herpes simplex virus (HSV) infections. Of 98 patients with leukaemia who underwent BMT, 73 received ACV (200 mg five times daily) and 25 were not given ACV. In the untreated group, 9 patients (36.0%) developed VZV infection by day 67 (median) and 3 patients died due to disseminated VZV infection. In the ACV-treated group, 18 patients (24.6%) developed VZV infection by day 150 (median) and there were no deaths. From July to December 1989, nine cases of VZV infections (eight patients and one nurse) were reported in the haematological ward of the hospital. All cases originated in the conventionally ventilated areas of the ward while no VZV infections were reported in the 14 patients who occupied the LAF rooms during the same period.