Diagnosis of herpes simplex virus in the era of polymerase chain reaction.
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Herpes Simplex↗
Biomedical subjects
David W Kimberlin
Publications and source records attributed to David W Kimberlin.
Antiviral therapies in children: has their time arrived?
The increase in the number and classes of antiviral agents that has occurred since the 1980s is remarkable. The rapid expansion in therapeutic options for previously untreatable illnesses challenges clinicians to gain familiarity and experience with these new drugs, especially with regard to their use in children. This article describes the clinical utilities, pharmacokinetics, and adverse effects of these new drugs to empower practitioners to use them appropriately.
Anti-HIV Agents↗
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↗
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↗
Herpes simplex virus infections in neonates and early childhood.
Of the commonly considered congenital infections, those caused by cytomegalovirus (CMV), syphilis, and herpes simplex virus (HSV) are frequently (CMV, HSV) or exclusively (syphilis) acquired sexually by the mother, with subsequent transmission to the developing fetus. Of the other commonly considered congenital infections, including rubella and toxoplasma infections, the mother is exposed to the infectious agent via interpersonal or environmental contacts. Unlike each of these other pathogens, which are transmitted transplacentally to the developing fetus following maternal infection though, HSV usually is transmitted perinatally as the neonate is exposed to the virus during passage through an infected birth canal. This difference in timing of acquisition of infection has had important consequence in the therapeutic advances achieved during the last 30 years in the management of neonatal HSV infections. Because the time period between the acquisition of infection and initiation of effective antiviral therapy is shorter in neonatal herpes than in congenital toxoplasmosis or CMV infections, the outcomes of therapy have the potential to be markedly different. This article will summarize the current state of neonatal HSV disease presentation, diagnosis, and management.
Adult↗
Diagnosis of herpes simplex virus infections of the CNS.
Advances in the diagnosis of herpes simplex virus infections of the CNS have occurred rapidly over the past 10 years. The development and application of PCR technology to the detection of herpes simplex virus DNA from cerebrospinal fluid has resulted in tremendous improvements in the management of patients with suspected herpes simplex virus CNS infections, not the least of which is decreasing the necessity for invasive brain biopsy to establish the diagnosis. The pace of discovery has continued in recent years with the development of more rapid DNA amplification techniques that do not require postamplification analysis using amplified products (real-time PCR). However, despite the power of these new diagnostic modalities, test results must always be considered in the context of the patient, and physician judgment should never be usurped by technological advances. This article will summarize the advances in the diagnosis of herpes simplex virus CNS disease within the context of how these advances can enhance the care of individual patients.
Animals↗
Detection of cytomegalovirus (CMV) DNA by polymerase chain reaction is associated with hearing loss in newborns with symptomatic congenital CMV infection involving the central nervous system.
OBJECTIVE: The study sought to determine the relationship between cytomegalovirus (CMV) viremia during early infancy and clinical and laboratory outcome events, particularly hearing loss in infants with symptomatic congenital CMV infection involving the central nervous system (CNS). STUDY DESIGN: A total of 147 infant patients were enrolled prospectively in 2 clinical trials evaluating ganciclovir for the treatment of symptomatic congenital CMV infection involving the CNS. Aliquots of serum collected at enrollment in either of the 2 trials were available from 50 of the infants, and the degree of viremia was determined by real-time quantitative polymerase chain reaction. RESULTS: Of the 50 infants from whom serum samples were available, 37 had detectable CMV DNA in the serum sample collected at enrollment and were classified as viremic. Viremic infants were more likely to have (1) hearing loss both at enrollment (P = .045) and at the 6-month follow-up testing (P = .035) and (2) other indicators of active CMV disease, including elevated levels of alanine aminotransferase, petechial rash, and organomegaly. CONCLUSION: In children with symptomatic congenital CMV infection involving the CNS, viremia during early infancy is associated with hearing loss and systemic CMV disease.
Central Nervous System Diseases↗
Surveillance of clinical isolates of respiratory syncytial virus for palivizumab (Synagis)-resistant mutants.
Premature infants and those with chronic lung disease or congenital heart disease are at high risk of severe respiratory syncytial virus (RSV) disease. Palivizumab (Synagis), a humanized anti-RSV monoclonal antibody, has been used extensively since 1998 to prevent severe RSV disease in high-risk infants. To monitor for possible palivizumab-resistant mutants, an immunofluorescence binding assay that predicts palivizumab neutralization of RSV was developed. RSV isolates were collected at 8 US sites from 458 infants hospitalized for RSV disease (1998-2002). Palivizumab bound to all 371 RSV isolates able to be evaluated, including 25 from active-palivizumab recipients. The palivizumab epitope appears to be highly conserved, even in infants receiving prophylaxis with palivizumab.
Antibodies, Monoclonal↗
Clinical practice. Genital herpes.
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Adult↗
Current status of antiviral therapy for juvenile-onset recurrent respiratory papillomatosis.
Human papillomavirus (HPV) infections are among the most prevalent of the sexually transmitted diseases, with up to 75% of women in the United States acquiring genital HPV infection at some point in their lives. HPV infections of the genital tract are of medical and public health concern due to their propensity to lead to the development of cervical cancer, and because they can be transmitted to the respiratory tract of a newborn child, resulting in juvenile-onset recurrent respiratory papillomatosis (JO-RRP). JO-RRP is the second most common cause of hoarseness among pediatric patients, and is the most common benign neoplasm in the larynx. The traditional treatment for JO-RRP is the physical removal of the wart through laryngoscopy and surgical debulking of the airway papillomas. Papillomas frequently recur following surgical resection, however, often necessitating repeated ablative efforts to maintain a patent airway. In a minority of patients, surgical management must be supplemented with adjuvant medical therapy, with interferon being the best studied and most commonly utilized. Recently, a Phase II investigation of a therapeutic vaccine yielded promising results, and a Phase III evaluation of this therapeutic modality is planned. Other adjuvant treatments currently being utilized, but for which controlled data of benefit are lacking, include cidofovir, indole-3-carbinol, ribavirin, mumps vaccine, and photodynamic therapy. As with surgical management, viral persistence occurs following treatment with these adjuvant modalities, further contributing to the challenge of managing patients with this potentially devastating disease.
Antiviral Agents↗
Neonatal herpes simplex infection.
Tremendous advances have occurred over the past 30 years in the diagnosis and management of neonatal herpes simplex virus (HSV) disease. Mortality in patients with disseminated disease has decreased from 85 to 29%, and that in patients with central nervous system (CNS) disease has decreased from 50 to 4%. Morbidity has been improved more modestly: the proportion of patients with disseminated disease who are developing normally at 1 year has increased from 50 to 83%. While the proportion of patients with neurologic morbidity following CNS disease has remained essentially unchanged over the past three decades, the total number of patients who are developing normally following HSV CNS disease has increased due to the improved survival. Although additional therapeutic advances in the future are possible, more immediate methods for further improvements in outcome for patients with this potentially devastating disease lie in an enhanced awareness of neonatal HSV infection and disease. A thorough understanding of the biology and natural history of HSV in the gravid woman and the neonate provides the basis for such an index of suspicion and is provided in this article.
Herpes Simplex↗
Neonatal HSV infections: the global picture.
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Female↗
Effect of ganciclovir therapy on hearing in symptomatic congenital cytomegalovirus disease involving the central nervous system: a randomized, controlled trial.
OBJECTIVE: To evaluate the efficacy and safety of ganciclovir therapy in neonates with congenital cytomegalovirus (CMV) disease. STUDY DESIGN: Neonates with symptomatic CMV disease involving the central nervous system were randomly assigned to receive 6 weeks of intravenous ganciclovir versus no treatment. The primary end point was improved brainstem-evoked response (BSER) between baseline and 6-month follow-up (or, for patients with normal baseline hearing, normal BSER at both time points). RESULTS: From 1991 to 1999, 100 patients were enrolled. Of these, 42 patients had both a baseline and 6-month follow-up BSER audiometric examination and thus were evaluable for the primary end point. Twenty-one (84%) of 25 ganciclovir recipients had improved hearing or maintained normal hearing between baseline and 6 months versus 10 (59%) of 17 control patients (P=.06). None (0%) of 25 ganciclovir recipients had worsening in hearing between baseline and 6 months versus 7 (41%) of 17 control patients (P<.01). A total of 43 patients had a BSER at both baseline and at 1 year or beyond. Five (21%) of 24 ganciclovir recipients had worsening of hearing between baseline and > or =1 year versus 13 (68%) of 19 control patients (P<.01). A total of 89 patients had absolute neutrophil counts determined during the course of the study; 29 (63%) of 46 ganciclovir-treated patients had grade 3 or 4 neutropenia during treatment versus 9 (21%) of 43 control patients (P<.01). CONCLUSIONS: Ganciclovir therapy begun in the neonatal period in symptomatically infected infants with CMV infection involving the central nervous system prevents hearing deterioration at 6 months and may prevent hearing deterioration at > or =1 year. Almost two thirds of treated infants have significant neutropenia during therapy.
Antiviral Agents↗
Molecular diagnosis of viral infections of the central nervous system.
The development of techniques for the amplification of DNA and RNA opened the way for the creation of extremely specific, sensitive, and rapid diagnostic tests for the detection of viral infections of the central nervous system. Polymerase chain reaction (PCR) and reverse transcription PCR diagnostic assays have revolutionized the approach to the diagnosis of important viral pathogens--in particular, enteroviruses (EVs), herpes viruses, and JC virus (JCV). These molecular approaches to diagnosis have led to improvements in clinical outcome and patient care. Additionally, their use has permitted a better understanding of the natural history and clinical spectrum of the syndromes caused by these important human pathogens. This article summarizes the current understanding with regard to the available, molecularly based, diagnostic assays for the detection of EVs, herpes viruses, and JCV.
DNA, Viral↗
Herpes simplex virus infections of the central nervous system.
Herpes simplex virus (HSV) infections of the central nervous system (CNS) can occur within weeks after birth (neonatal HSV disease) or in childhood or adulthood [herpes simplex encephalitis (HSE)]. Most cases of neonatal HSV disease are caused by HSV type 2, whereas virtually all cases of HSE are caused by HSV type 1. Diagnostic advances made during the past decade include the application of polymerase chain reaction (PCR) technology to cerebrospinal fluid from patients with suspected HSV CNS disease to evaluate for the presence of HSV DNA. Although not foolproof, PCR is a powerful diagnostic tool that has supplanted brain biopsy as the modality of choice for diagnosing HSV CNS disease, in no small part because of the invasiveness of brain biopsy. PCR also can provide information regarding the therapeutic response to antiviral therapy. Efforts made during the past decade to improve the outcome of HSV CNS disease have focused on increased doses of intravenous acyclovir administered for longer durations of time. Although advances have been achieved, morbidity and mortality rates from neonatal HSV disease and HSE remain unacceptably high.
Acyclovir↗
Evaluation of multiple drug therapy in human immunodeficiency virus-infected pediatric patients.
BACKGROUND: An aggressive therapeutic approach for treatment of HIV in adults consists of combining five or more concurrent antiretrovirals. The clinical benefits of this regimen are often accompanied by increased toxicities. We report the safety and tolerance of multiple drug therapy in HIV-infected children. METHODS: A retrospective chart review was performed to identify HIV-infected children who received > or =5 concurrent antiretrovirals or 4 antiretrovirals plus hydroxyurea. Treatment success was defined as > or =1 log(10) decrease in plasma HIV RNA from baseline any time during multiple drug therapy. Toxicities were defined as a >Grade 2 change from baseline in laboratory values. RESULTS: Twelve patients received multiple drug therapy for 6 months, and 42% of patients continued to receive therapy for at least 1 year. No Grade 3 or 4 toxicities or laboratory abnormalities were reported. Treatment success occurred in 8 (83%) of 12 patients. Adherence was a determining factor in treatment success or failure. CONCLUSIONS: Treatment of HIV-infected children with multiple drug therapy was well-tolerated in this cohort. Treatment success occurred in most patients, with adherence affecting patients' likelihood of success. Larger controlled clinical trials in this patient population are necessary to determine whether the benefit of this therapeutic approach outweighs potential risks.
Adolescent↗
Double blind placebo-controlled trial of pleconaril in infants with enterovirus meningitis.
BACKGROUND: Enterovirus (EV) meningitis is common in infants and may have neurologic complications. Treatment of older children and adults with pleconaril has been associated with reduced severity and duration of symptoms. This study evaluated the pharmacokinetics, safety and efficacy of pleconaril in infants with EV meningitis. METHODS: Infants < or =12 months old with suspected EV meningitis were randomized 2:1 to receive pleconaril, 5 mg/kg/dose orally three times a day or placebo for 7 days. Evaluations included pharmacokinetic determinations, safety laboratory testing, serial culture and PCR assays and clinical evaluations. RESULTS: Of 21 evaluable subjects 20 were confirmed with EV infection (12 pleconaril, 8 placebo). Among pleconaril-treated subjects 26 of 29 peak and trough pleconaril levels exceeded the 90% inhibitory concentration for EVs. A median 3.5-fold drug accumulation occurred between Days 2 and 7. Pleconaril was well-tolerated, although twice as many adverse events occurred per subject in the pleconaril group. Serial cultures from the oropharynx, rectum and serum had low yield (< or =50%) and positivity generally persisted for <4 days in both groups. Serial PCR assays of culture-negative oropharyngeal and rectal specimens had high positivity rates (generally > or =50%) persisting through Day 14. No significant differences in duration of positivity by culture or PCR, hospitalization or symptoms were detected between groups. CONCLUSIONS: The dose of pleconaril studied provided sufficient plasma levels and was well-tolerated; however, drug accumulation was evident. The low yields of serial viral cultures, relatively short and benign clinical courses and the small number of subjects enrolled precluded demonstration of efficacy. If this medication is to be prescribed in infants, surveillance for toxicity related to drug accumulation will be necessary.
Administration, Oral↗
Impact of the rapid diagnosis of influenza on physician decision-making and patient management in the pediatric emergency department: results of a randomized, prospective, controlled trial.
OBJECTIVE: To determine the impact of the rapid diagnosis of influenza on physician decision-making and patient management, including laboratory tests and radiographs ordered, patient charges associated with these tests, antibiotics/antivirals prescribed, and length of time to patient discharge from the emergency department. METHODS: Patients aged 2 months to 21 years presenting to an urban children's teaching hospital emergency department were screened for fever and cough, coryza, myalgias, headache, and/or malaise. After obtaining informed consent, patients were randomized to 1 of 2 groups: 1) physician receives (physician aware of) the rapid influenza test result; or 2) physician does not receive (physician unaware of) the result. For patients in the physician aware group, nasopharyngeal swabs were obtained, immediately tested with the FluOIA test for influenza A and B, and the result was placed on the chart before patient evaluation by the attending physician. For the physician unaware group, nasopharyngeal swabs were obtained, stored according to manufacturer's directions, and tested within 24 hours. Results for the physician unaware group were not disclosed to the treating physicians at any time. The 2 resultant influenza-positive groups (aware and unaware) were compared for laboratory and radiograph studies and their associated patient charges, antibiotic/antiviral prescriptions, and length of stay in the emergency department. RESULTS: A total of 418 patients were enrolled, and 391 completed the study. Of these, 202 tested positive for influenza. Comparison of the 96 influenza-positive patients whose physician was aware of the result with the 106 influenza-positive patients whose physician was unaware of the result revealed significant reductions among the former group in: 1) numbers of complete blood counts, blood cultures, urinalyses, urine cultures, and chest radiographs performed; 2) charges associated with these tests; 3) antibiotics prescribed; and 4) length of stay in the emergency department. The number of influenza-positive patients who received prescriptions for antiviral drugs was significantly higher among those whose physician was aware of the result. CONCLUSIONS: Physician awareness of a rapid diagnosis of influenza in the pediatric emergency department significantly reduced the number of laboratory tests and radiographs ordered and their associated charges, decreased antibiotic use, increased antiviral use, and decreased length of time to discharge.
Adolescent↗