Empiric Acyclovir Therapy Research Articles

1670. It Is Likely Not HSV: Decreasing Empiric Acyclovir Use In Low-Risk Infants

Abstract Background Neonatal HSV infection is a rare but potentially devastating disease. Institutional practices regarding which neonates must be treated empirically with acyclovir varies. While some centers elect to treat all neonates presenting with fever or hypothermia, some treat only those considered at risk. Our goal was to decrease empiric acyclovir use in low-risk neonates admitted to the Infectious Disease (ID) ward. Methods Quality improvement initiative aimed to decrease acyclovir exposure in neonates 15 to 28 days old hospitalized on the ID ward for fever/hypothermia without a focus, risk factors, or clinical signs for HSV (Figure 1). Interventions included development of a risk stratification algorithm (Figure 2), consensus building among Emergency Medicine and ID providers, and order set implementation. We reviewed all neonates with HSV infections for delayed acyclovir initiation as a balancing measure. The pre-study baseline period was 2019 to 2020, and the study period was 2020, to March 31, 2023. Control charts were used to assess the interventions.Figure 1Key Driver Diagram.Figure 2Risk stratification algorithm for HSV empiric treatment in low-risk infants. Results The mean acyclovir use per quarter in neonates who met low risk criteria decreased from 79% during the baseline period (7/2019-6/2020) to 30% in the post-intervention period (7/2020-3/2023) (p = < 0.0001) (Figure 3). Most common reasons why patients failed low risk criteria were: CSF pleocytosis in the setting of a traumatic LP, minimally abnormal lab values (slightly increased ALT, slightly decreased platelets), no LP in well-appearing patient and alternative fever etiology (URI symptoms with positive respiratory infection array). There were no cases of delayed acyclovir initiation in patients with HSV disease. Only one patient with HSV disease fell within the age range but was admitted to the ICU following cardiac arrest and appropriately started on acyclovir therapy.Figure 3Control chart of empiric acyclovir use in low-risk infants. Conclusion Our algorithm, targeted to limit empiric acyclovir therapy in neonates with fever/hypothermia without a focus at low risk for HSV, led to a significant decrease in acyclovir exposure sustained for > 2 years after implementation. Interestingly, it also led to decreased in acyclovir use in patients who failed low risk criteria, but this did not result in missed diagnosis of HSV disease, likely because our algorithm was conservative and HSV infection is rare. Disclosures All Authors: No reported disclosures

State of the Art: Acute Encephalitis.

Encephalitis is a devastating neurologic disease often complicated by prolonged neurologic deficits. Best practices for the management of adult patients include universal testing for a core group of etiologies, including herpes simplex virus (HSV)-1, varicella zoster virus (VZV), enteroviruses, West Nile virus, and anti-N-methyl-D-aspartate receptor (anti-NMDAR) antibody encephalitis. Empiric acyclovir therapy should be started at presentation and in selected cases continued until a second HSV-1 polymerase chain reaction test is negative. Acyclovir dose can be increased for VZV encephalitis. Supportive care is necessary for other viral etiologies. Patients in whom no cause for encephalitis is identified represent a particular challenge. Management includes repeat brain magnetic resonance imaging, imaging for occult malignancy, and empiric immunomodulatory treatment for autoimmune conditions. Next-generation sequencing (NGS) or brain biopsy should be considered. The rapid pace of discovery regarding autoimmune encephalitis and the development of advanced molecular tests such as NGS have improved diagnosis and outcomes. Research priorities include development of novel therapeutics.

Clinical progress note: Evaluation and management of neonatal herpes simplex virus disease.

Clinical progress note: Evaluation and management of neonatal herpes simplex virus disease.

Factors Associated With HSV PCR CSF Testing and Empiric Acyclovir Therapy in Young Febrile Infants.

Herpes simplex virus (HSV) infection in infants is a devastating disease with an often subtle presentation. We examined cerebrospinal fluid (CSF) HSV PCR (polymerase chain reaction) testing and empiric acyclovir therapy in young febrile infants. Chart review identified hospitalized infants aged ≤60 days with fever ≥38°C who had undergone lumbar puncture. Previously published criteria were used to define patients at high risk for HSV. Primary outcomes were CSF HSV PCR testing and empiric acyclovir therapy. Of 536 febrile infants, 23% had HSV testing; empiric acyclovir was started in 15%. HSV testing and therapy were associated with younger age, seizure, maternal vaginal lesions, postnatal HSV contact, vesicles, poor tone, CSF pleocytosis, and enteroviral testing. Sixty-two percent of high-risk infants did not undergo HSV testing, and 75% did not receive acyclovir. High-risk infants were untested and untreated at relatively high rates. Evidence-based criteria to guide HSV testing and treatment are needed.

Prevalence of herpes simplex virus-1 in hospitalized adult patients with clinical diagnosis of meningoencephalitis using real-time polymerase chain reaction: A single-center, cross-sectional study.

Background:Early diagnosis of herpes simplex virus-1 (HSV-1) meningoencephalitis is very important because antiviral therapy significantly decreases mortality and morbidity. Polymerase chain reaction (PCR) is a reliable method with high sensitivity and specificity in detection of HSV-1. The aim of this study is to determine the prevalence of HSV-1 in patients with diagnosis of meningoencephalitis using real-time PCR.Materials and Methods:The cerebrospinal fluid samples were collected from 126 patients with clinical diagnosis of HSV-1 meningoencephalitis in Alzahra Referral Hospital in Isfahan, Iran. After deoxyribonucleic acid (DNA) extraction, real-time PCR was performed by fluorescence resonance energy transfer assay and participants underwent brain magnetic resonance imaging, as well.Results:Among 126 patients, 68.3% were male and 31.7% were female. The mean age of the participants was 41.96 ± 22.36 years. Most of the participants were in the age group of 20–29 years. Three patients (2.4%) had positive and 123 patients (97.6%) had negative HSV-1 DNA test. Among three positive cases, two were in the age group of 20–29 years and one in the age group of ≥80 years. No HSV-2 DNA was detected.Conclusion:According to the estimated prevalence of HSV-1 meningoencephalitis in the current study, it seems that the prevalence of HSV-1 meningoencephalitis is not too high in our community; therefore, initial empiric acyclovir therapy is frequently overused.

Perinatally-acquired herpes simplex virus infection and empiric acyclovir therapy

Perinatally-acquired herpes simplex virus infection and empiric acyclovir therapy

Rare Presentation of Acute Liver Injury From Herpes Simplex Virus-1 Hepatitis and Concomitant Acetaminophen Toxicity in an Immunocompetent Patient

Introduction: Herpes simplex virus-1 (HSV-1) is an established cause of acute liver injury (ALI) in immunocompromised patients; very rarely has it been described as a factor of ALI in an immunocompetent patient. While ALI offers a broad differential including blood flow, toxins, and viral etiologies; the evaluation often is deemed complete after establishing a single unifying diagnosis. Here, we present a case of ALI from HSV 1 in the background of acetaminophen toxicity in an immunocompetent patient. Case Report: Our patient was a 37-year-old female with no significant medical history, presented with 2-day history of malaise, mild nausea, and poor oral intake. Physical exam was remarkable for scleral icterus; no signs of encephalopathy. Vital signs were stable. Admission labs showed markedly elevated AST/ALT of 7147/6729, respectively, bilirubin was 3.8, and alkaline phosphatase was minimally elevated, suggesting marked hepatocellular insult. Initial INR was 6, Tylenol level 127. On presentation, the primary concern was related to Tylenol toxicity, and NAC therapy was initiated along with one dose of oral vitamin K. 24 hours later, liver functions worsened (AST/ALT: 11597/11032, Tbili 4.3, INR 7.7), ALI work-up was further pursued, including antibody and viral testing. In the mean time, empiric acyclovir therapy was started pending HSV test results, and arrangements were being made to transfer the patient to a liver transplant center. There was a suspicion for viral etiology due to the pattern of transaminases (AST >ALT). A day later, the labs started to trend down and transaminases began to improve. Eventually, the work-up was positive for HSV-1 IgG (>10.49) and IgM (1:40). ANA, AMA, anti-smooth muscle Ab, IGG subclass, Hep A-Ab, HepBsAg, Hep Bs Ab, Hep C Ab, LKMA were negative. The patient was observed in the hospital for 3 days more as the labs normalized and then discharged home on 2 weeks of acyclovir therapy. On follow-up exam, she had returned to baseline with no evident chronic liver disease. Conclusion: HSV 1 hepatitis is an extremely rare cause of acute liver injury in an immunocompetent patient. In a patient having acute liver injury, even in those with an apparently evident acetaminophen toxicity, it is important to look for other possible causes fulminant hepatitis and empirically start acyclovir therapy, especially when AST>ALT and LFTs worsen despite appropriate therapy on NAC. Strong consideration for liver biopsy should also be undertaken. It is also important to recognize that this patient did not have any signs of encephalopathy inspite of significant liver injury. This is an unusual presentation of acute liver injury from HSV 1 hepatitis along with concomitant Tylenol toxicity.

Time to Consider Empiric Acyclovir

Purpose: A 63-year-old female presented to the emergency department with a two-day history of fever of 101.9°F and worsening fatigue. She denied a history of liver disease and was otherwise in good health, aside from a history of arthritis. She denied any recent changes in medications, use of antibiotics or travel history. Urine toxicology screen, acetaminophen level and hepatitis A-C serology were negative. Her laboratory assessment was notable for AST 4755 IU/L, ALT 3569 IU/L and an INR of 1.4. She was admitted into her local hospital and started on intravenous N-acetylcysteine. Overnight, she developed subtle changes in behavior without any change in level of consciousness. She was subsequently transferred to a liver transplant center. Upon arrival, the patient was oriented, but very somnolent, and remained febrile at 103.1°F. Physical exam was negative for stigmata of chronic liver disease, rash or asterixis. Laboratory assessment revealed total bilirubin 0.6 mg/dl, AST 7392 IU/L, ALT 5942 IU/L, INR of 2.2, WBC 2900 cells/ mm3, hemoglobin 16 g/dL and platelets of 29,000/mm3. Abdominal ultrasound showed a normalappearing liver with normal hepatic and portal flow. Further history from family revealed the patient was taking oral prednisone the past few weeks for chronic joint pain. Given this history, combined with fever, leukopenia and anicteric hepatitis, she was started on empiric IV acyclovir for possible herpes simplex virus (HSV)-induced liver failure. She underwent expedited liver transplant evaluation. A trans-jugular liver biopsy revealed minimal inflammation with scattered hepatocyptes with glassy nuclear inclusions, azonal areas of necrosis and positive HSV stain. Her serum HSV DNA testing by PCR was 1.2 x 10ˆ6 copies/ml, although her initial HSV IgM was within reference range. Her laboratory values normalized completely within 15 days, and she was discharged to a local rehab center. HSV-induced liver failure accounts for only 1% of all ALF, but confers a mortality rate of 75%. Although immunocompetent patients can be affected, 75% of affected patients are immunosuppressed or pregnant in the third trimester. Patients who present with fever, vesicular skin lesions, leukopenia and anicteric hepatitis need to be considered for empiric acyclovir therapy and transferred to a liver transplant center. Serological testing with antibodies against HSV in the serum is nonspecific and has low utility in early treatment decisions. Confirmation of diagnosis is best performed with liver biopsy and serum HSV PCR. Empiric therapy with acyclovir for patients at risk may obviate the need for liver transplantation.

Non-immune hydrops fetalis caused by herpes simplex virus type 2 in the setting of recurrent maternal infection

We report a case of non-immune hydrops fetalis (NIHF) caused by herpes simplex virus type 2 (HSV-2) in an infant whose mother had recurrent HSV-2 infection. In spite of prematurity, severe disseminated infection and hydrops, the infant survived and was neurologically intact. HSV-2-induced NIHF is extremely rare, particularly in the setting of recurrent maternal infection, and this case is, to our knowledge, the first report of a surviving infant. HSV-2 should be considered in the differential diagnosis of NIHF and early initiation of empiric acyclovir therapy is recommended in this setting, pending the results of virologic diagnostic tests.

Delayed Acyclovir Therapy and Death Among Neonates With Herpes Simplex Virus Infection

To determine the association of delayed acyclovir therapy with death among neonates with herpes simplex virus (HSV) infection. A multicenter, retrospective, cohort study was conducted between January 1, 2003, and December 31, 2009, with 1086 neonates (age: ≤28 days) with HSV infection from 41 tertiary care children's hospitals. Early acyclovir therapy was defined as initiation of intravenous acyclovir treatment within 1 day after hospital admission, and delayed acyclovir therapy was defined as initiation of treatment >1 and ≤7 days after hospital admission. Multivariate logistic regression models determined the association between delayed acyclovir therapy and death, with the use of propensity scores for each neonate's likelihood of receiving delayed acyclovir treatment to control for differences in illness severity between groups. The median age was 10 days. Delayed acyclovir therapy was administered to 262 neonates (24.1%). In most cases (86.2%) of delayed receipt, acyclovir administration occurred on the second or third day of hospitalization. The overall mortality rate was 7.3% (95% confidence interval: 5.8%-9.0%); 9.5% of those who received delayed acyclovir treatment and 6.6% of those who received early acyclovir treatment died. In a multivariate analysis, delayed acyclovir therapy was associated with significantly greater odds of death (adjusted odds ratio: 2.63 [95% confidence interval: 1.36-5.08]) compared with early acyclovir therapy. In this multicenter observational study of neonates with HSV infection, delayed initiation of acyclovir therapy was associated with in-hospital death. Our data support the use of empiric acyclovir therapy for neonates undergoing testing for HSV infection.

Herpes Simplex Virus Infection in Young Infants During 2 Decades of Empiric Acyclovir Therapy

To describe the clinical presentation of HSV-infected young infants and to seek distinctive features that could permit a targeted approach to empiric use of acyclovir. Case study of neonatal HSV during a 22-year period of an institutional strategy of consistent use of acyclovir empirically in all infants with onset of an illness at ≤ 21 days of age for which antibiotics were given empirically. Multiple sources were used to optimize HSV case data, and to estimate the rate of HSV infection in empirically treated infants. A total of 32 infants with perinatally acquired HSV infection were identified. All received acyclovir empirically at admission. At presentation, 50% of infants had only nonspecific complaints, which was fever in 75%. After testing, 75% of infants with HSV had central nervous system (CNS) infection, including 40% who presented with mucocutaneous lesions, 83% with seizures, and 94% with nonspecific complaints. Cerebrospinal fluid (CSF) polymerase chain reaction confirmed CNS infection in 16 of 22 (73%) patients tested. Cultures of mucocutaneous lesion yielded HSV in 8 of 10 cases, but culture of CSF was negative in all 26 cases tested, and screening cultures of unaffected mucosal sites were the only HSV-confirmatory test in a single patient. Laboratory and CSF findings were not distinctive in patients with HSV. Age of ≤ 21 days at onset of symptoms captured 90% of all infants with HSV and 94% of those with nonspecific complaints. An estimated 1.3% of empirically treated patients had HSV infection. Early manifestations of perinatally acquired HSV are frequently nonspecific, yet CNS infection is common. Empiric acyclovir strategy narrowly restricted to infants with onset of illness at ≤ 21 days of age, who would receive antibiotics empirically, captured 90% of HSV cases and anticipated a rate of HSV CNS infection similar to that of bacterial meningitis.

Herpes simplex virus hepatitis: An analysis of the published literature and institutional cases

Hepatitis is a rare complication of herpes simplex virus (HSV), often leading to acute liver failure (ALF), liver transplantation (LT), and/or death. Our aim was to identify variables associated with either survival or progression (death/LT), based on an analysis of cases in the literature and our institution. A total of 137 cases (132 literature, 5 institutional) of HSV hepatitis were identified. The main features at clinical presentation were fever (98%), coagulopathy (84%), and encephalopathy (80%). Rash was seen in less than half of patients. Most cases (58%) were first diagnosed at autopsy and the diagnosis was suspected clinically prior to tissue confirmation in only 23%. Overall, 74% of cases progressed to death or LT, with 51% in acyclovir-treated patients as compared to 88% in the untreated subjects (P=0.03). Variables on presentation associated with death or need for LT compared to spontaneous survival: male gender, age>40 yr, immunocompromised state, ALT>5,000 U/L, platelet count<75x10(3)/L, coagulopathy, encephalopathy, and absence of antiviral therapy. In conclusion, HSV hepatitis has a high mortality and is often clinically unsuspected. Patients who are male, older, immunocompromised, and/or presenting with significant liver dysfunction are more likely to progress to death and should thus be evaluated for LT early. Based on the frequent delay in HSV diagnosis, low risk-benefit ratio, and significantly improved outcomes, empiric acyclovir therapy for patients presenting with ALF of unknown etiology is recommended until HSV hepatitis is excluded.

Use of the polymerase chain reaction in the diagnosis of herpes simplex encephalitis: a decision analysis model

Purpose: To evaluate the utility of an assay based on a polymerase chain reaction (PCR) of cerebrospinal fluid in the management of patients with suspected herpes simplex encephalitis. Methods: A decision model was constructed and used to compare a PCR-based approach with empiric therapy. Inputs required by the model included the sensitivity (96%) and specificity (99%) of PCR (derived from review of the literature), the prevalence of herpes simplex encephalitis (5%, based on the actual prevalence at Barnes Hospital among patients treated empirically with acyclovir), the outcomes for patients with and without herpes simplex encephalitis (derived from clinical studies of the Collaborative Antiviral Study Group and the actual experience at Barnes Hospital), and the average duration of empiric acyclovir therapy for patients with possible herpes simplex encephalitis (5.3 days based on actual experience at Barnes Hospital). Results: Using these input values, the decision model predicted better outcomes with empiric therapy. However, low rates of inappropriate discontinuation of empiric therapy in patients with herpes simplex encephalitis or improved diagnosis and outcome resulting from a negative PCR assay result in patients without herpes simplex encephalitis led to better outcomes with the PCR-based approach. The PCR-based approach was associated with 9.2 fewer doses of acyclovir per patient. Conclusion: Based on the decision model using conservative assumptions, a PCR-based approach can yield better outcomes and reduced acyclovir use compared with empiric therapy.