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Biomedical subjects

Richard J Whitley

Publications and source records attributed to Richard J Whitley.

At least 19 recordsLinked to original sources
PubMed2007

Recommendations for the management of herpes zoster.

The objective of this article is to provide evidence-based recommendations for the management of patients with herpes zoster (HZ) that take into account clinical efficacy, adverse effects, impact on quality of life, and costs of treatment. Systematic literature reviews, published randomized clinical trials, existing guidelines, and the authors' clinical and research experience relevant to the management of patients with HZ were reviewed at a consensus meeting. The results of controlled trials and the clinical experience of the authors support the use of acyclovir, brivudin (where available), famciclovir, and valacyclovir as first-line antiviral therapy for the treatment of patients with HZ. Specific recommendations for the use of these medications are provided. In addition, suggestions are made for treatments that, when used in combination with antiviral therapy, may further reduce pain and other complications of HZ.

2-Aminopurine↗
PubMed2006

Lessons learned from reconstructing the 1918 influenza pandemic.

The "Spanish influenza" pandemic of 1918 was the most devastating influenza epidemic reported in history and killed >30 million people worldwide. The factors contributing to the severe pathogenicity of this influenza virus are of great interest, because avian influenza viruses circulating today pose the threat of a new pandemic if they develop sustained human-to-human transmissibility. Recent characterization of the 1918 virus has illuminated which determinants may be the cause of virulence. Here, we wish to shed light on what has been learned to date about the 1918 virus with regard to pathogenicity and transmissibility, to supplement our understanding of the determinants of human virulence and transmission of pandemic influenza viruses. Monitoring the sequences of avian influenza viruses for genetic changes and diversity may help us to predict the risks that these viruses pose of causing a new pandemic.

Animals↗
PubMed2006

Prevention and treatment of influenza in high-risk groups: children, pregnant women, immunocompromised hosts, and nursing home residents.

The pediatric population experiences preventable hospitalizations and serves as a reservoir for influenza and its transmission to other children as well as adults. As a consequence, the Advisory Committee on Immunization Practices has recommended initiating influenza immunization of children as young as 6 months of age through 23 months of age and, recently, up to 5 years of age. However, immunization of older children has not yet become a priority of the US Public Health Service. As a consequence, the importance of antiviral agents, particularly neuraminidase (NA) inhibitors, cannot be overemphasized. From an epidemiological perspective, influenza resulted in higher childhood mortality than did Bordetella pertussis infection in 2003-2004. During that season, 153 children died of influenza, and two-thirds were <5 years of age. Importantly, nearly 50% of these children were previously healthy, with no underlying illness. Currently, 2 NA inhibitors are approved for the treatment of influenza in children. Zanamivir is approved for children >7 years of age, and oseltamivir is approved for children >1 year of age. Arguably, the younger children are at particular risk for influenza complications and hospitalization. In placebo-controlled studies in children >1 year of age, oseltamivir therapy accelerated resolution of clinical illness and defervescence and decreased both the incidence of otitis media and the concomitant use of antibiotics. However, oseltamivir is not currently approved for children <1 year of age. Three clinical toxicology studies identified neurotoxicity in newborn rats administered this medication. In these preclinical toxicology studies, the dose of oseltamivir exceeded that which would be used in humans. In addition, the metabolism of oseltamivir is different in rats than in humans. A key component of influenza therapy is the possibility for development of resistance. Although in studies performed in North America, resistance was not a frequent event, it has been documented in Japanese children treated with this medication; the adequacy of the dose used has been questioned. Children represent only one unique study population among others. Individuals who are at increased risk for influenza infection include the elderly, the immunocompromised, and pregnant women. Collectively, antiviral medications must be evaluated in populations in which they have not yet been assessed. The development of additional antiviral drugs is an important recommendation for the future, so that antiviral resistance can be circumvented. Similarly, availability of drugs for children <1 year of age is mandatory.

Adolescent↗
PubMed2006

Seasonal and pandemic influenza: recommendations for preparedness in the United States.

There is a continued need to improve the state of preparedness for a potential influenza pandemic in the United States despite the publication of a pandemic influenza plan by the Department of Health and Human Services. Of particular importance are the sense of urgency for a coordinated response plan, an allocation of adequate funds to deal with this issue, and the need for a national leader to coordinate the development and execution of a national plan, including its relationship to the control of seasonal influenza. In addition, an infrastructure needs to be established in the United States to enable the rapid development and large-scale production of a safe and effective vaccine for new influenza strains; methods to treat influenza pneumonia need to be evaluated; a coordinated public health response needs to be defined; a nationally developed blueprint to deal with logistics of pandemic prevention is required; and there is a need to establish reliable communication systems on a national and local basis, to provide accurate information to the lay public, health care workers, and the agricultural sector.

Antiviral Agents↗
PubMed2006

Seasonal and pandemic influenza preparedness: a global threat.

The increase in the incidence of avian influenza worldwide in both poultry and humans introduces the potential for another influenza A pandemic that could pose a significant threat to both human health and the global economy. The impact of the next influenza pandemic will be influenced, in part, by how well the medical, government, business, and lay communities are prepared. Despite the additional tools and resources that have become available since prior epidemics, there are limits to the quantity of antiviral drugs that can be manufactured and concerns over the current vaccine production systems. Despite these challenges, there is an opportunity to take action before the emergence of a pandemic influenza strain and, possibly, to prevent its spread or at least mitigate its impact on the world. In February 2006, a group of representatives from federal, state, and local governments; professional bodies; academia; and the pharmaceutical industry met to review the current state of preparedness in the United States for a potential influenza pandemic and its relationship to seasonal influenza. The goal of the meeting was to examine the recently revised US Department of Health and Human Services plan for preparedness and response to an influenza pandemic and to make recommendations to actualize this plan at the state and local levels.

Animals↗
PubMed2006

Recurrent benign lymphocytic meningitis.

Recurrent benign lymphocytic meningitis is a recurring, typically innocuous, painful form of aseptic meningitis. This syndrome is associated with transient neurological symptoms in one-half of afflicted patients. The causative agent is usually herpes simplex virus type 2, which can be confirmed by detection of viral DNA in the cerebrospinal fluid using polymerase chain reaction. Clinical disease resolves spontaneously; however, acyclovir, valacyclovir, and famciclovir have been administered to some patients for both episodic therapy and suppression of recurrences. This therapy is thought to be beneficial, although there is no controlled trial data to support efficacy and safety.

2-Aminopurine↗
PubMed2006

Herpes simplex encephalitis: adolescents and adults.

Herpes simplex encephalitis (HSE) remains one of the most devastating infections of the central nervous system despite available antiviral therapy. Children and adolescents account for approximately one third of all cases of HSE. Clinical diagnosis is suggested in the encephalopathic, febrile patient with focal neurologic signs. However, these clinical findings are not pathognomonic because numerous other diseases in the central nervous system can mimic HSE. Neurodiagnostic evaluation can provide support for the diagnosis by the demonstration of temporal lobe edema/hemorrhage by magnetic resonance image scan and spike and slow-wave activity on electroencephalogram. In the current era, the diagnostic gold standard is the detection of herpes simplex virus (HSV) DNA in the cerebrospinal fluid by polymerase chain reaction (PCR). Although PCR is an excellent test and preferable to brain biopsy, false negatives can occur early after disease onset. Acyclovir is the treatment of choice and is administered at 10 mg/kg every 8 h for 21 days. Even with early administration of therapy after the disease onset, nearly two thirds of survivors have significant residual neurologic deficits. Current investigative efforts are assessing the prognostic value of quantitative PCR detection of viral DNA at the onset of therapy as well as at the completion of therapy and the contribution of prolonged antiviral therapy to improved neurologic outcome.

Adolescent↗
PubMed2006

Regulatory challenges: lessons from recent West Nile virus trials in the United States.

Delays in research on emerging infections could deprive the public of appropriate therapies. This report describes challenges encountered in implementing two multicenter protocols of West Nile virus (WNV) infections in the United States during 2003. Protocol development times, federal regulatory approvals, and local Institutional Review Boards (IRB) approvals were compiled. Twenty eight institutions participated in a natural history study and 27 in a therapeutic trial of WNV developed through the National Institute of Allergy and Infectious Disease Collaborative Antiviral Study Group (CASG). The CASG compiled protocol development times, federal regulatory approvals, and local IRB approvals. Additional information on the local IRB process was obtained by survey of the investigators. Because of the lengthy development and approval process, protocols were distributed after the start of the epidemic season, most sites were unable to enroll subjects at the peak of the season, and a number of sites lacked IRB approval at the end of the season.

Clinical Protocols↗
PubMed2006

Serial passage through human glioma xenografts selects for a Deltagamma134.5 herpes simplex virus type 1 mutant that exhibits decreased neurotoxicity and prolongs survival of mice with experimental brain tumors.

Previous studies have described in vitro serial passage of a Deltagamma(1)34.5 herpes simplex virus type 1 (HSV-1) strain in SK-N-SH neuroblastoma cells and selection of mutants that have acquired the ability to infect and replicate in this previously nonpermissive cell line. Here we describe the selection of a mutant HSV-1 strain by in vivo serial passage, which prolongs survival in two separate experimental murine brain tumor models. Two conditionally replication-competent Deltagamma(1)34.5 viruses, M002, which expresses murine interleukin-12, and its parent virus, R3659, were serially passaged within human malignant glioma D54-MG cell lines in vitro or flank tumor xenografts in vivo. The major findings are (i) viruses passaged in vivo demonstrate decreased neurovirulence, whereas those passaged in vitro demonstrate a partial recovery of the neurovirulence associated with HSV-1; and (ii) vvD54-M002, the virus selected after in vivo serial passage of M002 in D54-MG tumors, improves survival in two independent murine brain tumor models compared to the parent (unpassaged) M002. Additionally, in vitro-passaged, but not in vivo-passaged, M002 displayed changes in the protein synthesis profile in previously nonpermissive cell lines, as well as early U(S)11 transcription. Thus, a mutant HSV-1 strain expressing a foreign gene can be selected for enhanced antitumor efficacy via in vivo serial passage within flank D54-MG tumor xenografts. The enhanced antitumor efficacy of vvD54-M002 is not due to restoration of protein synthesis or early U(S)11 expression. This finding emphasizes the contribution of the in vivo tumor environment for selecting novel oncolytic HSV specifically adapted for tumor cell destruction in vivo.

Animals↗
PubMed2006

Oncolytic HSV-1 for the treatment of brain tumours.

The prognosis for patients diagnosed with malignant glioma, the most common primary tumour of the central nervous system, remains poor despite decades of research and advances in surgery, radiation and chemotherapy. The development of new approaches for the treatment of these tumours has led to the emergence of oncolytic viral therapy, with the use of conditionally replicating viruses, as a potential new intervention. Herpes simplex virus type 1 has emerged as the leading candidate oncolytic virus, with six different trials either completed or underway for patients with malignant glioma. In this review, the background of this approach will be discussed, followed by a discussion of the clinical trials, as well as potential directions for future trials.

Brain Neoplasms↗
PubMed2005

Genetically engineered herpes simplex viruses that express IL-12 or GM-CSF as vaccine candidates.

We are using genetically modified, conditionally replicating herpes simplex virus (HSV) that express either interleukin (IL)-12 or granulocyte macrophage-colony stimulating factor (GM-CSF) as live, attenuated vaccine candidates for protection against HSV infection and/or disease. We report the following: (1) animals previously vaccinated with these candidate vaccines exhibited dose-dependent protection after intranasal, intraperitoneal or intracranial challenge with the highly virulent E377-MB wild-type HSV-1; (2) the IL-12 expressing virus (M002) consistently conferred protection at lower immunization doses than GM-CSF expressing virus (M004); (3) between 80 and 100% protection from E377-MB challenge was conferred after intramuscular immunization of mice with any of the three Deltagamma1 34.5 HSV, as opposed to 50% protection elicited after immunization with wild-type HSV-1 (F); and (4) latent virus was not detected at a higher rate in animals immunized and subsequently challenged with E377-MB than in immunized animals alone. These data suggest that conditionally replicating, cytokine-expressing HSV are able to elicit protective immune responses while retaining safety in an experimental murine model.

Animals↗
PubMed2005

A randomized, open-label study to evaluate the safety and pharmacokinetics of human hepatitis C immune globulin (Civacir) in liver transplant recipients.

Chronic hepatitis C is the most common indication for liver transplantation, but viral recurrence is universal and progressive graft injury occurs in most recipients. Our aim was to assess the safety, pharmacokinetics (PK), and antiviral effects of high doses of a human hepatitis C antibody enriched immune globulin product (HCIG) in patients undergoing liver transplantation for chronic hepatitis C. This was a multicenter, randomized, open-label, controlled trial conducted at 4 transplant centers in the United States. A total of 18 patients with chronic hepatitis C, who underwent liver transplantation, were randomized to receive low-dose HCIG (75 mg/kg) or high-dose HCIG (200 mg/kg), or no treatment. A total of 17 infusions of HCIG were administered in each treated patient over 14 weeks using a time-dependent dosing strategy based on the PK of anti-hepatitis B immune globulin in liver transplant recipients. Hepatitis C virus levels, liver enzymes, and liver biopsies were obtained serially throughout the study period. PK profiles of HCV antibodies were determined on days 4, 10, and 98. HCIG infusions were safe and tolerated. The infusion rate could not be maximized because of symptoms for 18% to 30% of the doses. The half-life of HCIG was extremely short immediately after transplantation but was gradually prolonged. In the high-dose group, serum alanine aminotransferase (ALT) levels normalized in most subjects and no patient developed hepatic fibrosis. However, serum HCV RNA levels were not suppressed at either dose. In conclusion, HCIG, an anti-HCV enriched immune globulin product, appears to be safe in patients with chronic hepatitis C undergoing liver transplantation. Further studies are required to determine whether the drug has beneficial effects in this group of patients.

Adult↗
PubMed2005

Enhanced inhibition of syngeneic murine tumors by combinatorial therapy with genetically engineered HSV-1 expressing CCL2 and IL-12.

Herpes simplex viruses type 1 (HSV-1) that lack the gamma(1)34.5 gene are unable to replicate in the central nervous system (CNS), but maintain replication competence in actively dividing tumors. To determine if antitumor therapy by M002, a gamma(1)34.5(-) HSV that expresses interleukin-12 (IL-12), could be augmented by combinatorial therapy with another gamma(1)34.5-deleted HSV-1 engineered to express the chemokine CCL2, Neuro-2a tumors were established subcutaneously in the syngeneic A/J mouse strain. Tumors received multiple injections intratumorally either of saline, the parent, non-cytokine-expressing virus R3659, M002, M010 (gamma(1)34.5(-) HSV expressing CCL2), or a combination of M002 and M010. Efficacies were evaluated by monitoring inhibition of tumor growth over time. Results demonstrated the following: (1) inhibition of tumor growth was most pronounced in tumors treated with a combination of M002 and M010; (2) enhanced tumor growth inhibition for the combinatorial treatment group was statistically significant compared to either M002 or M010 alone; and (3) the variability between slopes of the tumor growth rates within an individual treatment group appeared to be virus-dependent, and was reproducible between experiments. Our results demonstrate that combinatorial cytokine/chemokine gamma(1)34.5(-) HSV therapies can provide superior antitumor effects in experimental tumors as a model for malignancies arising in the brain.

Animals↗
PubMed2005

Neonatal herpes: what have we learned.

Neonatal herpes simplex virus (HSV) infection usually is acquired during the birth process, as the neonate comes in contact with the virus during passage through an infected birth canal. After an incubation period which can last as long as 2 to 4 weeks, neonatal HSV disease then manifests in 1 of 3 ways: (1) disseminated disease, with visceral organ involvement (including infection of the brain in two-thirds to three-quarters of patients); (2) central nervous system disease (with no other visceral organ involvement, but with skin lesions in two-thirds of patients); or (3) disease limited to the skin, eyes, and/or mouth (ie, SEM disease). Diagnostic advances in recent years have focused primarily on applying polymerase chain reaction technology to babies suspected of having neonatal HSV disease. Treatment of neonatal HSV disease with intravenous acyclovir has improved the likelihood of survival substantially, although neurologic morbidity remains a common sequelae, especially among survivors of central nervous system disease. Despite these advances, the duration of time from onset of symptoms and initiation of antiviral therapy has remained unchanged for the past 20 years. The surest way to improve outcomes rapidly at this point is to raise awareness of neonatal HSV disease, resulting in the establishment of earlier diagnoses and more rapid institution of antiviral therapy. In the longer term, development of a bedside nucleic acid detection kit for real-time detection of HSV DNA in the maternal genital tract at the time of delivery could identify which babies are at risk of developing neonatal HSV disease.

Acyclovir↗
PubMed2005

Herpes simplex encephalitis: children and adolescents.

Herpes simplex encephalitis (HSE) remains one of the most devastating infections of the central nervous system despite available antiviral therapy. Children and adolescents account for approximately one third of all cases of HSE. Clinical diagnosis is suggested in the encephalopathic, febrile patient with focal neurologic signs. However, these clinical findings are not pathognomonic because numerous other infections in the central nervous system can mimic HSE. Support for the diagnosis from a neurodiagnostic perspective is aided by the demonstration of disease of the temporal lobe by magnetic resonance image scan and spike and slow-wave activity on electroencephalogram. In the current era, the gold standard for establishing diagnosis is the detection of herpes simplex virus DNA in the cerebrospinal fluid by polymerase chain reaction (PCR). Although PCR is an excellent test and far more desirable than brain biopsy, false negatives can occur early after disease onset. Current therapeutic management calls for the administration of acyclovir at 10 mg/kg every 8 hours for 21 days. Even with early administration of therapy after the onset of disease, nearly two thirds of survivors will have significant residual neurologic deficits. Recent investigative efforts are assessing the value of PCR detection of viral DNA at the completion of therapy and the value of prolonged antiviral therapy.

Adolescent↗
PubMed2005

Neonatal herpes should be a reportable disease.

Neonatal herpes is a devastating disease, the most serious complication of genital herpes, one of the most common serious congenital or perinatal infections, and the most frequent complication of sexually transmitted infections among children. Nevertheless, neonatal herpes is not reportable to health authorities in most states. The potential for prevention has been enhanced by recent diagnostic and therapeutic advances, and the disease meets widely accepted criteria for reporting, including incidence rates that exceed those of comparable conditions, epidemiologic instability, disease severity, direct and indirect socioeconomic costs, concern by persons at risk, the potential for prevention by public health interventions, and the prospect that the resulting data would influence public health policy. The absence of national surveillance contributes to beliefs by healthcare providers and the public health community that genital and neonatal herpes are uncommon conditions that affect small segments of society, beliefs that directly interfere with prevention. Neonatal herpes should be a reportable condition.

Antiviral Agents↗