[Clinical features of acyclovir encephalopathy without acute kidney injury].

INTRODUCTION: Few reports have described acyclovir (ACV) encephalopathy without acute kidney injury (AKI). OBJECTIVE: This study clarified the clinical features of ACV encephalopathy without AKI compared to that with AKI. METHODS: Creatinine (Cre) levels were measured on admission. After admission, Cre was measured in a timely manner for the first seven hospital days. The minimum Cre level in these measurements was then determined. ACV encephalopathy was defined when two criteria were met: 1) neurological symptoms appeared after valacyclovir (VACV) administration, and 2) neurological symptoms improved after VACV discontinuation. AKI was defined when the Cre level on admission was >1.5 times higher than the minimum Cre level. The subjects were divided into AKI and non-AKI groups based on these findings. RESULTS: Eighteen patients had ACV encephalopathy (5 males, mean age 81.3±5.5 years old). All patients were prescribed VACV 3,000 mg/day. The minimum Cre was 1.93±1.76 mg/dL. AKI occurred in 10 (56.6%) patients. VACV was discontinued in all patients, and emergency hemodialysis treatment was administered in 10 (55.6%) patients. All patients recovered. Compared to the AKI group, the non-AKI group had a lower history of taking a Ca-blocker (33.3% vs 80.0%, p=0.092), a lower rate of emergency dialysis (16.9% vs 70.0%, p=0.059) and a longer time to clinical improvement (3.67±1.86 vs 2.20±0.63 days, p=0.073). CONCLUSION: ACV encephalopathy without AKI is characterized by a low rate of emergency dialysis, which may be linked to a prolonged duration of symptoms.

Serious neurological adverse events in immunocompetent children and adolescents caused by viral reactivation in the years following varicella vaccination.

Serious adverse events following vaccination include medical complications that require hospitalisation. The live varicella vaccine that was approved by the Food and Drug Administration in the United States in 1995 has an excellent safety record. Since the vaccine is a live virus, adverse events are more common in immunocompromised children who are vaccinated inadvertently. This review includes only serious adverse events in children considered to be immunocompetent. The serious adverse event called varicella vaccine meningitis was first reported in a hospitalised immunocompetent child in 2008. When we carried out a literature search, we found 15 cases of immunocompetent children and adolescents with varicella vaccine meningitis; the median age was 11 years. Eight of the children had received two varicella vaccinations. Most of the children also had a concomitant herpes zoster rash, although three did not. The children lived in the United States, Greece, Germany, Switzerland, and Japan. During our literature search, we found five additional cases of serious neurological events in immunocompetent children; these included 4 cases of progressive herpes zoster and one case of acute retinitis. Pulses of enteral corticosteroids as well as a lack of herpes simplex virus antibody may be risk factors for reactivation in immunocompetent children. All 20 children with adverse events were treated with acyclovir and recovered; 19 were hospitalised and one child was managed as an outpatient. Even though the number of neurological adverse events remains exceedingly low following varicella vaccination, we recommend documentation of those caused by the vaccine virus.

Resorbable nanofibrous membranes for local and sustained co-delivery of acyclovir and ketorolac in herpes therapy.

Herpes simplex and herpes zoster are both viral infections caused by members of the herpesvirus family. The former is characterized by painful, fluid-filled blisters or sores on the skin and mucous membranes, while the latter presents as a painful rash with blisters, typically occurring in a single band or patch along one side of the body. The treatment remains a challenge since current antiviral therapy via oral administration may lead to unfavorable side effects such as headaches, nausea, and diarrhea. This study used electrospinning to develop biodegradable nanofibrous poly(lactic-co-glycolic acid) (PLGA) membranes for delivery of both acyclovir and ketorolac. The structure of the spun nanofibers was assessed via scanning electron microscopy (SEM), and the appearance of loaded acyclovir and ketorolac in the nanofibers was confirmed with Fourier-transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC). Release profiles of these drugs from the nanofibrous membranes were assessed using in vitro elution studies, high-performance liquid chromatography (HPLC) assays, and in vivo drug release patterns. The electrospun nanofibers had a size range of 283-725 nm in diameter, resembling the extracellular matrix of natural tissue and demonstrated excellent flexibility and extensibility. Notably, the drug-eluting nanofibers exhibited an extended release of high levels of acyclovir and ketorolac over a 21-day period. Thus, biodegradable drug-eluting membranes with a prolonged drug release could be a potential therapeutic approach for treating herpes infections.

Analyses of the onset mechanisms of cardio-stimulatory action by aciclovir.

Cardio-stimulatory actions of aciclovir have been considered to primarily depend on the sympathetically-mediated reflex resulting from its hypotensive effect. To further clarify onset mechanisms of the cardio-stimulatory actions, we initially studied them using isoflurane-anesthetized dogs under thorough ß1-adrenoceptor blockade with atenolol (1 mg/kg, i.v.) (n = 4). Aciclovir (20 mg/kg/10 min, i.v.) decreased mean arterial blood pressure by 10 mmHg, whereas it increased heart rate by 10 bpm and maximum upstroke velocity of ventricular pressure by 928 mmHg/s, and shortened AH interval by 2 ms, indicating that cardio-stimulatory actions were not totally abolished by ß1-adrenoceptor blockade. Then, unknown mechanisms of cardio-stimulatory action were explored. Since aciclovir has a similar chemical structure to theophylline, in silico molecular docking simulation was performed, indicating aciclovir as well as theophylline possesses strong likelihood of interactions with phosphodiesterase 1A, 1C and 3A. Indeed, aciclovir inhibited phosphodiesterase 1A derived from the bovine heart (n = 4), moreover it exerted positive chronotropic action on the atrial tissue preparation of rats along with an increase of tissue cyclic AMP concentration (n = 4). These results indicate that cardio-stimulatory actions of aciclovir could result from not only hypotension-induced, reflex-mediated increase of sympathetic tone but also its inhibitory effects on phosphodiesterase in the heart.

Development and Validation of an HPLC-UV Method for the Quantification of Acyclovir and Ganciclovir in the Plasma of Pediatric Immunocompromised Patients.

Acyclovir and ganciclovir comprise the prophylaxis and treatment of herpesvirus and cytomegalovirus infections occurring in immunocompromised patients. Their therapeutic drug monitoring is fundamental because of interindividual variability leading to side effects and drug resistance and is performed through several techniques, such as liquid chromatography coupled with UV spectrophotometry (HPLC-UV) or mass spectrometry (LC-MS/MS). Therefore, we developed and validated a low-cost, non-time-consuming, and low-sample-consuming HPLC-UV method. Briefly, 100 µL of sample was used for sample preparation, mainly consisting of precipitation through organic solvent. In total, 20 µL was injected into the instrument. Chromatographic separation was obtained eluting mobile phases A (10 mM ammonium formiate 0.01% formic acid) and B (acetonitrile) on a Poroshell 120 SB-C8 2.1 × 150 mm, 2.7 µm for 12 min isocratically (97:3; A:B) at a flow rate of 0.2 mL/min. The linearity range (0.5-40 mg/L) of the method allowed us to quantify both the Cmin and Cmax of acyclovir and ganciclovir. Plasma concentrations measured on a small cohort of patients undergoing acyclovir (31) and ganciclovir (9) treatment by the proposed method and the LC-MS/MS methods, already in use, were significantly correlated. The proposed HPLC-UV method may be implemented in diagnostics as an alternative method in case of the unavailability of the LC-MS/MS system.

Acyclovir-Induced Nephrotoxicity in Adults with Viral Encephalitis.

OBJECTIVE: To determine the frequency of parenteral Acyclovir-induced Acute Kidney Injury (AKI) in patients with viral encephalitis. STUDY DESIGN: Descriptive study. Place and Duration of the Study: Department of Neurology, Liaquat National Hospital, Karachi, from January to December 2021. METHODOLOGY: A total of 89 suspected and proven cases of encephalitis receiving IV Acyclovir were collated. All had extensive medical histories and underwent CSF studies with +/- brain imaging. CSF routine and viral PCR were done. Acyclovir-induced AKI was defined as a rise in serum creatinine of >0.3 mg/dl in 48 h or by ≥1.5 times the baseline value, and its severity was staged into 1 (risk), 2 (injury), and 3 (failure) according to the KDIGO guidelines (Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group, 2012). Patients' variables, including age, gender, presenting features, comorbid conditions, and CSF findings, were divided into two groups, i.e. with and without AKI. RESULTS: This research included 89 patients with a mean age of 48 years. AKI occurred in 34 patients (38.2%). The frequency of AKI with Stage 1 was 24%, Stage 2 was 44%, and Stage 3 was 32%; approximately two-thirds of cases were in Stage 2 and 3 (p >0.05). Five patients (5.6%) from Stage 3, required dialysis. CONCLUSION: AKI is an important adverse effect of parenteral acyclovir, which necessitates its early identification and timely management. Renal function monitoring is essential for patients on Acyclovir treatment as they are at risk for AKI. KEY WORDS: Acyclovir, Acute kidney injury, Viral encephalitis, Creatinine, Kidney Disease Improving Global Outcomes.

Herpes Simplex Keratitis as a Complication of Pterygium Surgery.

BACKGROUND Infectious keratitis after pterygium surgery is a rare but potentially devastating complication. The present study presents 5 cases of herpes simplex keratitis (HSK) after pterygium surgery. CASE REPORT This study was conducted in our clinic in a 5-year period from February 2017 to September 2021. The 5 patients were men, aged between 42 and 73 years, with no prior history of herpes simplex virus (HSV) infections. Symptoms appeared near 1 month (median 30 days, range 10 to 70 days) after primary pterygium surgery. Diagnosis was based on clinical symptoms and laboratory test results, such as tear HSV-sIgA, corneal tissue polymerase chain reaction, and next-generation sequencing of metagenomics. The epithelial (1/5) and stromal (4/5) subtypes of HSK were identified. The patients received topical ganciclovir gel, immunosuppressive eyedrops, and oral acyclovir tablets, along with additional surgical interventions if necessary. Three were healed with conservative therapy, 1 eye required amniotic membrane transplantation due to corneal melt, and 1 was perforated and followed by corneal grafting. Finally, a literature review of previous publications on HSK after ocular surgeries was conducted. CONCLUSIONS HSK is a rare but serious complication that can arise after uneventful pterygium surgery. It is worthy of attention that both epithelial and stromal forms can occur. Timely diagnosis and treatment are crucial to prevent unfavorable outcomes. Consequently, routine corneal fluorescein staining, tear sIgA examination, and corneal scraping for polymerase chain reaction or next-generation sequencing of metagenomics should be performed in any suspected cases.

Efficacy of photobiomodulation therapy in recurrent herpes labialis management: a randomized controlled trial.

OBJECTIVES: This study is aimed at assessing the therapeutic efficacy of photobiomodulation therapy (PBMT) for the management of recurrent herpes labialis (RHL) by evaluating both pain and clinical recovery. MATERIAL AND METHODS: A randomized, double-blind, controlled trial was conducted on 40 patients with RHL, and they were randomly divided into two groups, where 20 patients received treatment with PBMT (650 nm, 100 mW, 4.7 J/cm2), continuous mode, for 120 s, and placebo cream, while another 20 patients (control group) were treated with acyclovir cream 5% (5 times/5 days) and passive laser. Pain was assessed at five different times. The day when the complete disappearance of the pain was observed and the day when the crust fell off spontaneously were also recorded. RESULTS: The pain level in the control group was significantly higher than that in the PBMT group after the second application of the laser, while the differences were not significant between the two groups at other times. The pain in the PBMT group disappeared faster than that in the control group, but the difference was not significant in terms of clinical recovery. CONCLUSIONS: Photobiomodulation therapy of herpes labialis reduced pain significantly faster than acyclovir, but there was no difference in healing time between the groups in light of the parameters used in this study. CLINICAL RELEVANCE: PBMT is a promising treatment that may be an effective alternative to acyclovir in the management of recurrent herpes labialis. TRIAL REGISTRATION ISRCTN: com ID: ISRCTN87606522.

Kaposi varicelliform eruption: an unusual presentation caused by varicella zoster virus in a healthy adult patient - a case report.

BACKGROUND: Kaposi Varicelliform Eruptions (KVE), also known as eczema herpeticum, is a rare and potentially life-threatening dermatological condition primarily attributed to herpes simplex virus (HSV) infection, with less frequent involvement of Coxsackie A16, vaccinia, Varicella Zoster, and smallpox viruses. Typically associated with pre-existing skin diseases, especially atopic dermatitis, KVE predominantly affects children but can manifest in healthy adults. Characterized by painful clusters of vesicles and sores on the skin and mucous membranes, it often masquerades as other dermatological disorders. Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used for pain relief and inflammation, though their potential role as KVE triggers remains uncertain. CASE REPORT: Here, we present a case of an 18-year-old female with KVE attributed to Varicella Zoster virus (VZV) and successfully treated with oral acyclovir within a week, underscoring the significance of early recognition and intervention. KVE can manifest with systemic symptoms like fever, fatigue, and lymphadenopathy and may involve multiple organ systems, necessitating possible antibiotic use for complications. CONCLUSION: This case underscores the importance of prompt KVE identification and consideration of antiviral therapy to enhance patient outcomes. Further research is warranted to elucidate predisposing factors for this rare condition.

Adjunctive Intravenous Immunoglobulin and Glucocorticoid Therapy in Severe Herpes Simplex Encephalitis with Excellent Outcome Begs for Larger Trials Evaluating Immunomodulatory Therapy.

BACKGROUND Despite the preponderance of evidence of immune-driven pathophysiology of disease in herpes simplex virus-1 (HSV-1) encephalitis, current treatment paradigms do not officially recommend adjunctive immunomodulatory therapy in addition to acyclovir. This may in part explain the poor long-term outcomes in patients with severe HSV encephalitis. This report is of a 21-year-old man presenting with a 4-day history of nausea, headache, and fever and a diagnosis of HSV-1 encephalitis. CASE REPORT We describe the case of a young male with clinically and radiographically severe HSV-1 encephalitis diagnosed by PCR of cerebrospinal fluid (CSF), who demonstrated immediate improvement upon treatment with intravenous immunoglobulin (IVIG, 0.5 g/kg daily ×3 days) in addition to acyclovir and dexamethasone therapy. Acyclovir therapy was extended beyond 21 days due to persistently positive HSV-1 CSF PCR. He developed N-methyl-D-aspartate (NMDA) receptor antibodies at 6 weeks, but his long-term outcome far exceeded expectations. While some of his neurological deficits appear to be permanent, he is living a normal life. CONCLUSIONS Overwhelming evidence demonstrates that brain injury due to HSV encephalitis is driven by immune reactions stimulated by HSV rather than HSV itself. Nevertheless, use of immunomodulatory therapy such as glucocorticoids and IVIG are left to the discretion of individual clinicians rather than being recommended in treatment guidelines, which instead recommend acyclovir therapy. The present case highlights the potential role of immunomodulatory therapy with IVIG in HSV encephalitis and the importance of early diagnosis and treatment.

Atypical cutaneous findings of hand-foot-mouth disease in children: A systematic review.

INTRODUCTION: Hand-foot-mouth disease (HFMD) is a common childhood infectious disease. Atypical skin findings of HFMD, often associated with coxsackievirus A6 (CVA6), were first reported in 2008, with increasing reports worldwide since. Atypical lesions of HFMD often involve sites beyond the palms and soles and tend to have unusual, polymorphic morphology. METHODS: A systematic review was conducted on clinical features and outcomes of pediatric HFMD with atypical cutaneous manifestations. RESULTS: Eighty-five studies were included, representing 1359 cases with mean age 2.4 years and a male predominance of 61%. The most reported morphologies were vesicles (53%), papules (49%), and bullae (36%). Other morphologies included eczema herpeticum-like (19%), purpuric/petechial (7%), and Gianotti Crosti-like (4%). Common atypical sites included the arms and/or legs (47%), face (45%), and trunk (27%). CVA6 was identified in 63% of cases. Symptoms resolved in a mean of 10 days. Overall, 16% of cases received treatment, most commonly with acyclovir, intravenous antibiotics, or topical steroids. The most common complications were nail changes (21%) and desquamation (4%) which occurred a mean of 3 and 2 weeks after symptoms, respectively. CONCLUSION: Due to unusual morphologies resembling other conditions, HFMD with atypical cutaneous findings may be misdiagnosed, leading to inappropriate and unnecessary investigations, hospitalization, and treatment. Greater awareness of atypical presentations of HFMD is warranted to improve patient care and counseling on infection control precautions.

Recalcitrant ulcerative genital herpes in an immunocompetent individual treated successfully with imiquimod.

BACKGROUND: This case report describes the successful use of imiquimod to treat genital herpes in an immunocompetent individual with acyclovir-resistant HSV. CASE REPORT: A 32 year old male patient, presented with asymptomatic non-healing ulcers over the genital region for 2 years. The ulcers initially responded to acyclovir but became persistent after a few months. He also received multiple courses of antibiotics. On examination, the patient had bilateral inguinal lymphadenopathy and multiple painless ulcers over the coronal sulcus. Routine investigations were normal. The patient was treated with oral and intravenous acyclovir but showed no response. He was then started on topical imiquimod cream applied on alternate days. After one week, the patient presented with pain, redness, burning sensation, and fresh ulcer over the glans which were suspected to be imiquimod-induced irritant reaction or ulcer. Imiquimod was withheld for one week and then restarted at a twice-weekly schedule. After 1 month and 7 days of treatment with imiquimod at a twice-weekly schedule, there was healing of the ulcers. CONCLUSION: This case report illustrates the efficacy of imiquimod cream as a topical treatment for genital herpes simplex in an immunocompetent patient who had previously been unresponsive to treatment with acyclovir.

Post-Exposure Prophylaxis for Varicella-Zoster Virus Exposure in High-Risk Children.

BACKGROUND: Post-exposure prophylaxis (PEP) with varicella immunoglobulin is recommended to minimize risk of varicella complications for high-risk children. However, providers frequently use alternatives like acyclovir or intravenous immunoglobulin. METHODS: A retrospective cohort study was conducted of PEP for varicella in children from January 2009 to December 2019. Data were provided by 47 children's hospitals who participate in the Pediatric Health Information Systems database. Patients with clinical encounters for varicella exposure were reviewed. Choice of varicella PEP regimens, including differences by underlying condition and institution, and incidence of varicella disease were determined. RESULTS: A total of 1704 patients with first clinical encounters for varicella met inclusion criteria. Of these patients, 509 (29.9%) were prescribed PEP after varicella exposure, and 65 (3.8%) ultimately had a subsequent encounter for varicella disease. Of 509 patients who received PEP, acyclovir was most frequently prescribed (n = 195, 38.3%), followed by varicella immunoglobulin (n = 146, 28.7%), IVIG (n = 115, 22.6%), and combination therapy (n = 53, 10.4%). The highest proportion of varicella immunoglobulin use (10/20, 50%) was amongst children with diagnoses of rheumatological/gastrointestinal conditions. The highest proportion of acyclovir use (29/684, 4.2%) was amongst children with diagnoses of oncology/stem cell transplant conditions. The proportion of patients who subsequently had clinical encounters for varicella disease was highest for Acyclovir (30/195, 15.4%) followed by varicella immunoglobulin (5/146, 3.4%), combination therapy (2/53, 3.8%), and intravenous immunoglobulin alone (0/115) (P < .0001). CONCLUSIONS: Varicella PEP in high-risk children was highly varied among children's hospitals. In our dataset, use of acyclovir was associated with a higher rate of subsequent encounters for Varicella disease.

Detection of varicella-zoster virus in two dermatomes of herpes zoster duplex bilateralis in an immunocompetent host.

An 85-year-old woman with no history of herpes zoster (HZ) presented with a primary lesion of erythema and blistering on her left thigh and a secondary similar lesion on her right chest which had appeared at 4 and 3 days before presentation, respectively. Tzanck smears for both lesions were positive, revealing multinucleated giant cells. Immunochromatography to detect varicella-zoster virus (VZV) antigen (DermaQuick®VZV) showed positive on the left thigh at initial onset but negative on the right chest at subsequent onset. The latter repeatedly tested negative for VZV by DermaQuick®VZV. A skin biopsy of the subsequent onset area revealed giant cells, and inclusion bodies were observed in the epidermis. Immunohistochemical staining with anti-VZV antibody and polymerase chain reaction to detect VZV DNA were positive. The patient was diagnosed with HZ duplex bilateralis and treated with acyclovir. The right thoracic region of the posterior part of the lesion became negative for DermaQuick®VZV. It is thought that expression of viral antigens was suppressed in the right thoracic region, i.e., the late-onset area.

Cytokine storm and severe hepatitis in pregnancy due to herpes simplex virus 2.

CASE PRESENTATION: A pregnant woman developed hepatitis due to a herpes simplex virus 2 primary infection with a severe systemic inflammatory response. Treatment with acyclovir and human immunoglobulin was given and both mother and baby survived. PURPOSE: We provide the first description of the inflammatory response associated with herpetic hepatitis in pregnancy.

Analysis of antiviral drug properties of thymidine kinase of herpes B virus using recombinant herpes simplex virus 1.

IMPORTANCE: Zoonotic infection of humans with herpes B virus (BV) causes severe neurological diseases. Acyclovir (ACV) and ganciclovir (GCV), most frequently used as anti-herpes drugs, are recommended for prophylaxis and therapy in human BV infection. In this study, we examined the property of BV thymidine kinase (TK) against anti-herpes drugs using a recombinant herpes simplex virus type 1 (HSV-1) carrying BV TK gene. We found that HSV-1 carrying BV TK was similarly sensitive to GCV as HSV-1 carrying varicella zoster virus TK. In addition, we demonstrated that BV TK was not mutated in the GCV- and ACV-resistant HSV-1 carrying BV TK, suggesting that ACV- or GCV-resistant BV might be rare during treatment with these antiviral drugs. These data can provide a new insight into the properties of BV TK in terms of the development of drug resistance.

Signal mining study of severe cutaneous adverse events of valaciclovir or acyclovir based on the FAERS database.

OBJECTIVE: This study aimed to explore a comprehensive empirical investigation and assess SCARs related to valaciclovir or acyclovir based on FAERS database from FDA, thus providing a theoretical foundation for the rational application of drugs in clinic. METHODS: SCARs reports relevant to valaciclovir or acyclovir were searched in FAERS database from the 2004 Q1 to 2023 Q2. These data were further mined by a proportional analysis and Bayesian approach to detect signals of SCARs caused by two drugs. Meanwhile, the clinical characteristics, onset time, correlation, and stratification analysis of the two drugs in SCARs were analyzed. RESULTS: Both drugs exhibited positive signals for drug reaction with DRESS, AGEP, TEN, SJS-TEN overlap and SJS. The median onset time of SCARs caused by valaciclovir or acyclovir was 30 days vs 10 day for DRESS, 11 days vs 9 days for AGEP, 17 days vs 12 days (TEN) and 12 days vs 8 days (SJS). Excluding the effect of combinational drugs, there was an association between the two antiviral drugs and SCARs. CONCLUSION: By analyzing the FAERS database, the risk trends of SCARs caused by valaciclovir or acyclovir have been identified, providing valuable insights to recognize various types of SCARs in clinics.