Congenital herpes simplex with ophthalmic and multisystem features: a case report.

BACKGROUND: Neonatal herpes simplex virus (HSV) infection is rare and has significant morbimortality rates. Approximately 85% of newborns are infected intrapartum, and risk factors for mother-to-child transmission include vaginal delivery, primary maternal infection, and prolonged rupture of membranes. Neonatal HSV can manifest with isolated mucocutaneous lesions, neurological involvement, or disseminated disease. In general, herpetic infection can cause blepharoconjunctivitis or keratitis. We report a rare case of congenital herpes with ophthalmologic manifestations and multisystemic involvement. CASE PRESENTATION: A preterm infant, born at 32 weeks and 2 days, with presumed neonatal infection developed intestinal and respiratory complications, as well as hyperemic lesions on the left nostril and oral mucosa. An ophthalmological assessment was requested and brought up the suspicion of HSV infection, indicating empirical treatment with endovenous acyclovir. Later, a new ocular examination was suggestive of panuveitis. Afterward, serum IgM antibodies to HSV-1 and HSV-2 were positive. Proper antiviral therapy led to an improvement in the condition. DISCUSSION: Neonatal herpes is associated with a high risk of persistent skin lesions, long-term neurological disability and other lasting sequelae. It is essential to consider HSV infection in cases of neonatal conjunctivitis, especially in patients with an epithelial defect and no improvement after initial treatment with topical or systemic antibiotics. CONCLUSIONS: In the management of neonatal HSV, early diagnosis is essential for the timely initiation of antiviral therapy. Our report highlights that ocular assessment can be crucial in the correct diagnostic investigation of this condition.

The Many Faces of Neurological Neonatal Herpes Simplex Virus Infection.

This case series explores the various manifestations of central nervous system (CNS) involvement in neonatal herpes simplex virus (HSV) infection and highlights the challenges involved in their diagnosis and treatment. Neonatal HSV infection is a rare but serious condition that can have significant neurological consequences. The article presents three cases of neonatal HSV infection, all involving the CNS, each characterized by distinct clinical features and outcomes. Case 1 describes a three-week-old male with severe HSV meningoencephalitis resulting in poor response to treatment and death. Cases 2 and 3 describe younger neonates who presented early in the disease course with disseminated infection and skin, eye, and mouth (SEM) lesions. Although both patients had CNS involvement, their outcomes were remarkably favorable. The wide range of clinical presentations of CNS manifestations in neonatal HSV infection, ranging from nonspecific to evident neurological symptoms, underscores the need for a high index of suspicion and comprehensive evaluation to ensure early diagnosis and appropriate treatment. However, it also notes that even with timely treatment, some cases may still have a poor prognosis.

Management of oral herpes simplex virus infections: The problem of resistance. A narrative review.

Herpes Simplex Virus (HSV) type 1 (HSV-1) and type 2 (HSV-2) are among the most common human viral pathogens, affecting several billion people worldwide. Although in healthy patients clinical signs and symptoms of HSV infection are usually mild and self-limiting, HSV-infections in immunocompromised patients are frequently more aggressive, persistent, and even life-threatening. Acyclovir and its derivatives are the gold standard antiviral drugs for the prevention and treatment of HSV infections. Although the development of acyclovir resistance is a rather uncommon condition, it may be associated with serious complications, especially in immunocompromised patients. In this review, we aim to address the problem of drug resistant HSV infection and discuss the available alternative therapeutic interventions. All relative studies concerning alternative treatment modalities of acyclovir resistant HSV infection published in PubMed between 1989 to 2022 were reviewed. Long-term treatment and prophylaxis with antiviral agents predisposes to drug resistance, especially in immunocompromised patients. Cidofovir and foscarnet could serve as alternative treatments in these cases. Although rare, acyclovir resistance may be associated with severe complications. Hopefully, in the future, novel antiviral drugs and vaccines will be available in order to avoid the existing drug resistance.

Salvage Treatment of Refractory HSV Oral Lesions with Pritelivir in Allogeneic Hematopoietic Cell Transplant Recipients.

We present two allogeneic hematopoietic cell transplantation recipients (HCTr) treated with pritelivir for acyclovir-resistant/refractory (r/r) HSV infection based on the expanded access program of the pritelivir manufacturer. Outpatient treatment with pritelivir was administered, with partial response by week 1 of treatment and complete response by week 4 of treatment in both patients. No adverse events were noted. Pritelivir appears to be an effective and safe option for the management of acyclovir-r/r HSV infections in highly immunocompromised patients in an outpatient setting.

Superior antiviral activity of IFNß in genital HSV-1 infection.

Type I interferons (IFNs) present the first line of defense against viral infections, providing antiviral, immunomodulatory and antiproliferative effects. The type I IFN family contains 12 IFNα subtypes and IFNß, and although they share the same receptor, they are classified as non-redundant, capable to induce a variety of different IFN-stimulated genes. However, the biological impact of individual subtypes remains controversial. Recent data propose a subtype-specificity of type I IFNs revealing unique effector functions for different viruses and thus expanding the implications for IFNα-based antiviral immunotherapies. Despite extensive research, drug-resistant infections with herpes simplex virus type 1 (HSV-1), which is the common agent of recurrent orogenital lesions, are still lacking a protective or curing therapeutic. However, due to the risk of generalized infections in immunocompromised hosts as well as the increasing incidence of resistance to conventional antiherpetic agents, HSV infections raise major health concerns. Based on their pleiotropic effector functions, the application of type I IFNs represents a promising approach to inhibit HSV-1 replication, to improve host immunity and to further elucidate their qualitative differences. Here, selective IFNα subtypes and IFNß were evaluated for their therapeutic potential in genital HSV-1 infections. Respective in vivo studies in mice revealed subtype-specific differences in the reduction of local viral loads. IFNß had the strongest antiviral efficacy against genital HSV-1 infection in mice, whereas IFNα1, IFNα4, and IFNα11 had no impact on viral loads. Based on flow cytometric analyses of underlying immune responses at local and peripheral sites, these differences could be further assigned to specific modulations of the antiviral immunity early during HSV-1 infection. IFNß led to enhanced systemic cytokine secretion and elevated cytotoxic responses, which negatively correlated with viral loads in the vaginal tract. These data provide further insights into the diversity of type I IFN effector functions and their impact on the immunological control of HSV-1 infections.

Neonatal Herpes Simplex Virus: Cutaneous Recurrence Is Common on Stopping Prophylactic Suppression Therapy.

Neonatal herpes simplex virus (HSV) infection is a potentially devastating disease. Data on the recurrence of disease while on suppressive therapy are limited. We reviewed cases of neonatal HSV. Prematurity was associated with more recurrence. No systemic or CNS recurrence occurred, but there were frequent recurrences of skin lesions.

Monoclonal antibody therapy of herpes simplex virus: An opportunity to decrease congenital and perinatal infections.

The fetal/neonatal period represents both a unique window of opportunity for interventions as well as vulnerability to a number of viral infections. While Herpesviruses such as herpes simplex virus (HSV) are highly prevalent and typically of little consequence among healthy adults, they are among the most consequential infections of early life. Despite treatment with antiviral drugs, neonatal HSV (nHSV) infections can still result in significant mortality and lifelong neurological morbidity. Fortunately, newborns in our pathogen-rich world inherit some of the protection provided by the maternal immune system in the form of transferred antibodies. Maternal seropositivity, resulting in placental transfer of antibodies capable of neutralizing virus and eliciting the diverse effector functions of the innate immune system are associated with dramatically decreased risk of nHSV. Given this clear epidemiological evidence of reduced risk of infection and its sequelae, we present what is known about the ability of monoclonal antibody therapies to treat or prevent HSV infection and explore how effective antibody-based interventions in conjunction with antiviral therapy might reduce early life mortality and long-term morbidity.

Adenovirus-mediated RNA interference against herpes simplex virus infection in vitro.

INTRODUCTION: Herpetic keratitis caused by the herpes simplex virus (HSV) is the most common form of ocular herpes that causes corneal blindness. Although treatments for herpes keratitis have improved in recent years. there is still considerable room for new treatments against viral infection that shows great promise. The aim of the study was to evaluate the effect of RNA interference on HSV Type 1 (HSV1) infection in vitro, first prophylactically then therapeutically. MATERIAL AND METHODS: The highly conserved glycoproteins D (gD) and E (gE) were chosen as targets for this study. Different small interfering RNA (siRNA) duplexes that target gD and gE were designed and chemically synthesized. The recombinant adenovirus type 5 was developed and used as the vehicle with which we delivered the siRNA into the Vero cells infected with the HSV1 KOS strain. Evaluation of the efficacy of siRNA-mediated inhibition was performed either before virus inoculation (prophylactically) or after virus inoculation at the first appearance of lesions (therapeutically). The expression of messenger RNA encoding gD and gE was detected using a real-time polymerase chain reaction (qPCR). We analyzed HSV replication in Vero cells, cytotoxicity of HSV, and cell viability. RESULTS: When used prophylactically, the siRNA-targeting gD and gE created a more marked decrease in viral titer than when used therapeutically. The transfection of cells with recombinant adenovirus containing the siRNA expression cassette was associated with very low cytotoxicity. CONCLUSIONS: Adenovirus-mediated siRNA-targeting gD and gE genes effectively inhibit the replication of the HSV in Vero cells. In addition, these findings indicate that the prophylactic use of siRNA is far more effective at inhibiting HSV replication than the therapeutic use.

[Herpes simplex virus resistance to antivirals]. / Résistance des virus herpes simplex aux antiviraux.

Herpes simplex virus (HSV) infections remain an important cause of morbidity among immunocompromised patients, such as transplant recipients and human immunodeficiency virus [HIV]-infected individuals. Only few antiviral drugs are available to treat HSV infections: (val)acyclovir, foscarnet, and cidofovir. Prophylactic and curative antiviral treatments administered during prolonged periods among patients with altered T-cell immunity may lead to the emergence of HSV resistance to antivirals, contributing to a challenging therapeutic management of viral infection. The persistence of herpetic lesions after 10 days of well-conducted antiviral therapy is suggestive of viral resistance. Resistance to antivirals can be detected using genotypic methods (identifications of antiviral resistance-associated mutations by sequencing genes encoding viral proteins involved in the mechanism of action of antivirals) or phenotypic methods (measure of antiviral drug concentration inhibiting 50% of viral replication in cell culture). The prevalence of HSV resistance to acyclovir is below 1% in immunocompetent individuals, except those with herpetic keratitis for whom prevalence can reach 7%, and varies from 3.5% to 11% in immunocompromised patients. Adverse effects and the absence of eradication of viral latent infection constitute other limits to the use of antiviral drugs. New antiviral compounds undergoing clinical trials and novel potential viral targets seem very promising to enlarge the panel of efficient compounds to treat HSV infections.

Acute Kidney Injury During Treatment with Intravenous Acyclovir for Suspected or Confirmed Neonatal Herpes Simplex Virus Infection.

OBJECTIVE: To describe the epidemiology of and risk factors associated with acute kidney injury (AKI) during acyclovir treatment in neonates and infants. STUDY DESIGN: We conducted a multicenter (n = 4), retrospective cohort study of all hospitalized infants age <60 days treated with intravenous acyclovir (≥1 dose) for suspected or confirmed neonatal herpes simplex virus disease from January 2011 to December 2015. Infants with serum creatinine measured both before acyclovir (baseline) and during treatment were included. We classified AKI based on changes in creatinine according to published neonatal AKI criteria and performed Cox regression analysis to evaluate risk factors for AKI during acyclovir treatment. RESULTS: We included 1017 infants. The majority received short courses of acyclovir (median, 5 doses). Fifty-seven infants (5.6%) developed AKI during acyclovir treatment, with an incidence rate of AKI at 11.6 per 1000 acyclovir days. Cox regression analysis identified having confirmed herpes simplex virus disease (OR, 4.35; P = .002), receipt of ≥2 concomitant nephrotoxic medications (OR, 3.07; P = .004), receipt of mechanical ventilation (OR, 5.97; P = .001), and admission to an intensive care unit (OR, 6.02; P = .006) as risk factors for AKI during acyclovir treatment. CONCLUSIONS: Among our cohort of infants exposed to acyclovir, the rate of AKI was low. Sicker infants and those exposed to additional nephrotoxic medications seem to be at greater risk for acyclovir-induced toxicity and warrant closer monitoring.

Multitasking: Dual Leucine Zipper-Bearing Kinases in Neuronal Development and Stress Management.

The dual leucine zipper-bearing kinase (DLK) and leucine zipper-bearing kinase (LZK) are evolutionarily conserved MAPKKKs of the mixed-lineage kinase family. Acting upstream of stress-responsive JNK and p38 MAP kinases, DLK and LZK have emerged as central players in neuronal responses to a variety of acute and traumatic injuries. Recent studies also implicate their function in astrocytes, microglia, and other nonneuronal cells, reflecting their expanding roles in the multicellular response to injury and in disease. Of particular note is the potential link of these kinases to neurodegenerative diseases and cancer. It is thus critical to understand the physiological contexts under which these kinases are activated, as well as the signal transduction mechanisms that mediate specific functional outcomes. In this review we first provide a historical overview of the biochemical and functional dissection of these kinases. We then discuss recent findings on regulating their activity to enhance cellular protection following injury and in disease, focusing on but not limited to the nervous system.

Toll-like receptors as novel therapeutic targets for herpes simplex virus infection.

Seropositivity for HSV reaches more than 70% within the world population, and yet no approved vaccine exists. While HSV1 is responsible for keratitis, encephalitis, and labialis, HSV2 carriers have a high susceptibility to other STD infections, such as HIV. Induction of antiviral innate immune responses upon infection depends on a family of pattern recognition receptors called Toll-like receptors (TLR). TLRs bridge innate and adaptive immunity by sensing virus infection and activating antiviral immune responses. HSV adopts smart tricks to evade innate immunity and can also manipulate TLR signaling to evade the immune system or even confer destructive effects in favor of virus replication. Here, we review mechanisms by which HSV can trick TLR signaling to impair innate immunity. Then, we analyze the role of HSV-mediated molecular cues, in particular, NF-κB signaling, in promoting protective versus destructive effects of TLRs. Finally, TLR-based therapeutic opportunities with the goal of preventing or treating HSV infection will be discussed.

Bilateral Herpes Simplex Virus-related Peripheral Ulcerative Keratitis Leading to Corneal Perforation in a Patient with Primary Herpes Simplex Virus Infection.

PURPOSE: To present a case of bilateral peripheral ulcerative keratitis (PUK) caused by primary herpes simplex virus-1 (HSV-1) infection resulting in corneal perforation. CASE REPORT: A 24-year-old man presented at the eye casualty of our clinic, with a 20-day history of severe pain, redness, photophobia, and tearing in both of his eyes. Slit-lamp examination revealed bilateral superior corneal perforation. A laboratory work-up that included immunological testing for infectious and autoimmune factors showed primary HSV infection. Positive PCR analysis of corneal scrapings for HSV confirmed initial end-organ ocular infection. Because the patient showed progressive HSV-1-related PUK resulting in bilateral superior corneal perforation with iris prolapse, he was prescribed both systemic and topical acyclovir and prednisone. He then underwent bilateral surgical intervention, namely eccentric penetrating keratoplasty in one eye and a two step procedure in the other, whereby two corneal patch grafts and an amniotic membrane transplant were initially used, followed 1 month later by a large diameter penetrating keratoplasty. CONCLUSION: In cases of PUK, differential diagnosis should include infectious and autoimmune diseases. Primary HSV should also be considered as a potential cause of this form of keratitis, which, if left untreated, can lead to devastating outcomes. To our knowledge, this is the first published case of bilateral PUK caused by primary HSV-1 infection.

Nerve Regeneration in Conditions of HSV-Infection and an Antiviral Drug Influence.

Herpes simplex virus type I (HSV-I) is a latent neuroinfection which can cause focal brain lesion. The role of HSV-infection in nerve regeneration has not been studied so far. The aim of the work was to study sciatic nerve regeneration in the presence of HSV-infection and the influence of an antiviral drug. BALB/c line mice were divided into five groups. Group 1 animals were infected with HSV-I. After resolution of neuroinfection manifestations the sciatic nerve of these animals was crushed. Group 2 mice were administered acyclovir following the same procedures. Groups 3-5 mice served as controls. Thirty days after the operation distal nerve stumps and m.gastrocnemius were studied morphologically and biochemically. Ultrastructural organization of the sciatic nerve in control animals remained intact. Morphometric parameters of the nerves from the experimental groups have not reach control values. However, in the group 1 diameter of nerve fibers was significantly smaller than in the group 2. Both nerve regeneration and m.gastrocnemius reinnervation were confirmed. The muscle hypotrophy was found in groups 1, 2, and 3 (the muscle fibers diameter decreased). Metabolic changes in the muscles of the infected animals (groups 1 and 2) were more pronounced than in control groups 3 and 4. The levels of TBA-active products, conjugated dienes, carbonyl and SH-groups were reduced in m.gastrocnemius of the experimental groups, however no significant difference associated with acyclovir administration was found. HSV-infection is not limited to the local neurodegenerative changes in the CNS but affects regeneration of the injured sciatic nerve. Anat Rec, 301:1734-1744, 2018. © 2018 Wiley Periodicals, Inc.

A 20-year experience of ocular herpes virus detection using immunofluorescence and polymerase chain reaction.

BACKGROUND: To detect the presence of herpes virus in corneal scrapings/corneal grafts of suspected herpetic keratitis patients attending the outpatient department/casualty of the Dr Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi for the past 20 years with immunofluorescence assay and to analyse the efficacy of polymerase chain reaction over immunofluorescence for routine laboratory diagnosis in some of the specimens. METHODS: Corneal scrapings and corneal grafts were collected by the ophthalmologists from 1,926 suspected herpetic keratitis patients between 1996 and 2015, among whom 1,863 patients were processed with immunofluorescence assay and 302 patients were processed with polymerase chain reaction assay for the detection of herpes virus. Of the 302 patients, clinical specimens from 239 patients were analysed by both polymerase chain reaction and immunofluorescence assay. RESULTS: Of the 1,863 suspected herpetic keratitis patients diagnosed with immunofluorescence assay, 277 (14.9 per cent) were found positive for herpes simplex virus 1 antigen. Similarly, of the 302 suspected herpetic keratitis patients diagnosed by polymerase chain reaction, 70 (23.2 per cent) were found positive for herpes simplex virus DNA. Of the 239 patients diagnosed by both polymerase chain reaction and immunofluorescence assay, 35 (14.6 per cent) were found positive with immunofluorescence assay, 59 (24.7 per cent) were found positive with polymerase chain reaction, 30 (12.5 per cent) were positive with both immunofluorescence and polymerase chain reaction assay. CONCLUSION: Efficacy and accuracy of the polymerase chain reaction assay was greater compared to the immunofluorescence assay for detection of herpes virus in corneal scrapings/corneal grafts of suspected herpetic keratitis patients. Although the immunofluorescence assay is a rapid test for the detection of herpes virus in suspected herpetic keratitis patients, a combination of polymerase chain reaction with immunofluorescence assay will provide higher reliable and accurate results.

Neonatal Herpes Simplex Viral Infections and Acyclovir: An Update.

Neonatal herpes simplex virus (HSV) infections have high morbidity and mortality rates. Optimization of treatment and prevention strategies are imperative to improve the care and outcomes of neonates infected with HSV. Management of HSV includes reducing neonatal transmission, treating acute infections, and limiting adverse neurodevelopmental outcomes and future cutaneous outbreaks after acute infections. Transmission risk may be affected by route of delivery and maternal suppressive therapy. Neonatal HSV infections are divided into 3 categories: localized skin, eyes, or mouth; localized central nervous system; or disseminated infections. Parenteral acyclovir, the pharmacologic agent of choice, is used when treating each type of infection. However, dosage strategies and durations of therapy may vary based on disease state severity, presentation, and patient characteristics. Oral acyclovir may be used as suppressive therapy after acute treatment completion in specific neonatal populations, reducing long-term adverse neurodevelopmental outcomes and future skin eruptions. The mortality rate remains high even with treatment.

Distal Interphalangeal Joint Arthrodesis Complicated by Postoperative Infection: A Rare Presentation of Disseminated Herpes Simplex Virus.

Postoperative infection after elective arthrodesis of the interphalangeal joint is an uncommon complication often necessitating urgent debridement. We present the rare case of a female patient with a history of oral herpetic lesions, who underwent elective arthrodesis of the middle and index fingers for treatment of erosive osteoarthritis and subsequently developed a postoperative herpetic infection at the surgical site.

Long-term valacyclovir treatment and immune modulation for Herpes-associated erythema multiforme.

OBJECTIVE: Erythema multiforme (EM) is an immune-mediated condition characterized by the appearance of target-like lesions on the skin and often accompanied by erosions or bullae involving the oral, genital, and/or ocular mucosae. 70% of recurrent EM cases are associated with HSV reactivation and it is labelled as herpes-associated erythema multiforme (HAE M). Recurrences are seen in approximately 20-25% of EM cases and managing these conditions are challenging for both the patient and the doctor. The effectiveness of antiviral drugs is proven for Herpes simplex infection, however most patients use a multiplicity of alternative and complementary therapies. CLINICAL PRESENTATION: We present clinical data of 3 patients with recurrent HAE M managed by long-term valacyclovir therapy and immunostimulation with Echinacea or replacement immunoglobulin therapy in the case of IgG1 subclass deficiency. The presented cases have demonstrated that immune mechanisms are relevant for HAEM recurrences. CONCLUSIONS: The immune abnormalities, such as antibody deficiency, in the patients with HSV-associated EM can lead to frequent relapses of disease and should be evaluated. Long-term antiviral therapy with immunomodulation can control the relapses of HAEM.

Recurrent neonatal herpes simplex virus infection with central nervous system disease after completion of a 6-month course of suppressive therapy: Case report.

A boy at 12 days of age developed neonatal herpes simplex virus (HSV) type 2 infection with central nervous system (CNS) disease. After a 21-day course of high-dose intravenous acyclovir, the patient recovered with negative results for HSV DNA in serum and cerebrospinal fluid. Two weeks after a 6-month course of oral valacyclovir suppressive therapy with negative virological assessment, the disease recurred. Another 21-day course of intravenous acyclovir and subsequent 1-year course of oral suppressive therapy were completed. He showed mild developmental delay in language-social skills at 18 months of age. Although recurrences of neonatal HSV infection with CNS disease after suppressive therapy are uncommon, both clinical and virological assessments at the end of the suppressive therapy may be required. Administration of extended long-term suppressive ACV therapy should be considered to reduce the rate of recurrence.

Genital herpes.

Genital herpes is a relatively common infection caused by herpes simplex virus (HSV) type one or two (HSV-1, HSV-2) respectively. It is acquired most commonly via sexual activity. More recently there has been an increase in infections due to HSV-1. Most new cases of genital HSV are not diagnosed due to HSV infections having short-lived signs and symptoms, or in many instances are asymptomatic. Hence many people infected with HSV are unaware that they have it. The risk of transmission to a partner is highest during outbreak periods, when there are visible lesions, although genital HSV can also be transmitted during asymptomatic periods. Use of condoms and antiviral medications assist in preventing transmission. Antiviral agents are effective in controlling clinical episodes, but do not eradicate infection, which remains latent for the life of a patient. Despite the surge in vaccine research, there is unfortunately no readily available preventative or therapeutic vaccine for HSV to date.