Herpes Simplex Virus Infection Research Articles

PA08 Extensive congenital epidermal skin loss with sparing of the palms, soles and head: strikingly similar appearances in four patients with neonatal herpes simplex infection

PA08 Extensive congenital epidermal skin loss with sparing of the palms, soles and head: strikingly similar appearances in four patients with neonatal herpes simplex infection

Acyclovir Dosing Practices Across a Multicenter Cohort of Neonatal Intensive Care Units.

Acyclovir is the first-line therapy for neonatal herpes simplex virus infections. Therapy can mitigate morbidity and mortality but carries a risk for toxicity. We aimed to compare acyclovir dosing in neonatal intensive care units to published recommendations based on population pharmacokinetic (PopPK) analysis. We performed a multicenter cohort study of infants in neonatal intensive care units managed by the Pediatrix Medical Group from 1997 to 2020. We included all infants who received acyclovir with complete dosing information. Our primary outcome was the proportion of courses with dosing within 80%-120% of the PopPK recommended daily dose and at the recommended dosing frequency. We compared dosing before and after the publication of the 2014 PopPK recommendations using linear probability modeling. We identified 6862 infants with complete dosing information across 308 centers. Dosing met PopPK recommendations for 41% of treatment courses for infants <30 weeks postmenstrual age (PMA), 71% for infants 30 to <36 weeks PMA and <1% for infants ≥ 36 weeks PMA. Comparison of dosing from 1997 to 2013 with that from 2015 to 2020 showed a significant increase in dosing meeting PopPK recommendations for infants <30 weeks PMA (P = 0.008) and infants 30 to <36 weeks PMA (P = 0.02) but not infants ≥ 36 weeks PMA (P = 0.29). No significant increase in dosing meeting PopPK recommendations was seen for any PMA group when comparison was limited to more recent years (2008-2013 vs. 2015-2020). Dosing meeting PopPK recommendations increased over time for some PMA groups, but dosing different than PopPK recommendations remains common. More research is needed to clarify optimal dosing strategies in these infants.

Management of Pustules and Vesicles in Afebrile Infants ≤60 Days Evaluated by Dermatology.

To assess the management and outcomes of afebrile infants who received a pediatric dermatology consultation for pustules and/or vesicles. Medical records were reviewed for all infants 60 days of age or younger who received a pediatric dermatology consult across 6 academic institutions between September 1, 2013 and August 31, 2019 to identify those infants with pustules and/or vesicles. Of the 879 consults, 183 afebrile infants presented with pustules and/or vesicles. No cerebrospinal fluid cultures or blood cultures were positive for bacteria. No concordant positive urine cultures were identified in infants with cutaneous infection. Nine infants were diagnosed with herpes simplex virus (HSV). Five preterm infants were diagnosed with angioinvasive fungal infections. No serious bacterial infections attributable to a skin source were identified, yet 53% of these infants received parenteral antibiotics. HSV was diagnosed in 7% of this cohort, 77.8% (7/9) of whom were term infants and 22.2% (2 of 9) of whom were preterm. Angioinvasive fungal infection was diagnosed in 3%, all of whom (100%, 5 of 5) were extremely preterm at <28 weeks gestational age. These findings suggest that in full-term afebrile infants ≤60 days, the likelihood of a life-threatening etiology of isolated pustules or vesicles is low once HSV infection is excluded. In preterm infants with pustules and/or vesicles, a high index of suspicion must be maintained, and broad infectious evaluation is recommended. HSV testing is recommended for all infants with vesicles, grouped pustules and/or punched-out erosions.

Flexible nano-liposomes-encapsulated recombinant UL8-siRNA (r/si-UL8) based on bioengineering strategy inhibits herpes simplex virus-1 infection

Herpes simplex virus-1 (HSV-1) infection can cause various diseases and the current therapeutics have limited efficacy. Small interfering RNA (siRNA) therapeutics are a promising approach against infectious diseases by targeting the viral mRNAs directly. Recently, we employed a novel tRNA scaffold to produce recombinant siRNA agents with few natural posttranscriptional modifications. In this study, we aimed to develop a specific prodrug against HSV-1 infection based on siRNA therapeutics by bioengineering technology. We screened and found that UL8 of the HSV-1 genome was an ideal antiviral target based on RNAi. Next, we used a novel bio-engineering approach to manufacture recombinant UL8-siRNA (r/si-UL8) in Escherichia coli with high purity and activity. The r/si-UL8 was selectively processed to mature si-UL8 and significantly reduced the number of infectious virions in human cells. r/si-UL8 delivered by flexible nano-liposomes significantly decreased the viral load in the skin and improved the survival rate in the preventive mouse zosteriform model. Furthermore, r/si-UL8 also effectively inhibited HSV-1 infection in a 3D human epidermal skin model. Taken together, our results highlight that the novel siRNA bioengineering technology is a unique addition to the conventional approach for siRNA therapeutics and r/si-UL8 may be a promising prodrug for curing HSV-1 infection.

Late-Onset Concurrent Infection of Vaccine Strain VZV and HSV-1 after Varicella Vaccination in a Child with Natural killer T Cell Deficiency

AbstractWe describe a case with natural killer cell deficiency of late-onset Oka vaccine varicella zoster virus (VZV) strain and Herpes simplex virus-1 (HSV-1) dual infection resulting in fatal clinical course. An 18-month-old boy presented with a papulovesicular rash, mucocutaneous candidiasis, encephalopathy, and severe respiratory distress 6 months after receiving varicella vaccine. VZV and HSV-1 were analysed by real-time reverse-transcriptase polymerase chain reaction (RT-qPCR) and Oka vaccine strain of VZV by gene sequencing. HSV-1 and VZV dual infection was detected in the blood and skin samples by RT-qPCR. Gene sequencing of VZV isolated from vesicular lesions was compatible with the Oka vaccine strain. Flow cytometry revealed a natural killer deficiency, but whole exome analysis failed to identify an associated genetic defect. Vesicular rashes in immunocompromised patients who were inadvertently vaccinated should be taken seriously, and antiviral therapy should be prompt and aggressive.

A viral E3 ubiquitin ligase produced by herpes simplex virus 1 inhibits the NLRP1 inflammasome.

Guard proteins initiate defense mechanisms upon sensing pathogen-encoded virulence factors. Successful viral pathogens likely inhibit guard protein activity, but these interactions have been largely undefined. Here, we demonstrate that the human pathogen herpes simplex virus 1 (HSV-1) stimulates and inhibits an antiviral pathway initiated by NLRP1, a guard protein that induces inflammasome formation and pyroptotic cell death when activated. Notably, HSV-1 infection of human keratinocytes promotes posttranslational modifications to NLRP1, consistent with MAPK-dependent NLRP1 activation, but does not result in downstream inflammasome formation. We identify infected cell protein 0 (ICP0) as the critical HSV-1 protein that is necessary and sufficient for inhibition of the NLRP1 pathway. Mechanistically, ICP0's cytoplasmic localization and function as an E3 ubiquitin ligase prevents proteasomal degradation of the auto-inhibitory NT-NLRP1 fragment, thereby preventing inflammasome formation. Further, we demonstrate that inhibiting this inflammasome is important for promoting HSV-1 replication. Thus, we have established a mechanism by which HSV-1 overcomes a guard-mediated antiviral defense strategy in humans.

Viral Infection in Upper Gastrointestinal Tract

Viral infections of the upper gastrointestinal (GI) tract are not uncommon in clinical practice; however, these are frequently observed in immunocompromised patients and rarely in immunocompetent hosts. Compared with esophagitis, which may be associated with clinically significant outcomes, the stomach is a relatively rare site for opportunistic infections in immunocompetent patients. The most common clinically relevant upper GI tract viral infections include cytomegalovirus (CMV), Epstein-Barr virus (EBV), and herpes simplex virus infections. CMV esophagitis and gastritis, which primarily occur in immunocompromised patients, necessitate antiviral treatment, whereas immunocompetent patients typically respond to proton pump inhibitor administration. Most EBV-induced gastric infections are asymptomatic. However, EBV infection is a known etiological contributor to stomach cancer. EBV-associated gastric cancer shows distinctive clinical, pathological, genetic, and post-genetic mutation features and is therefore a clinically significant entity. Herpetic esophagitis usually affects immunocompromised patients and is uncommon in immunocompetent individuals. In this review, we discuss the general aspects and recent studies that have reported esophageal and gastric infections in immunocompromised patients.

Acyclovir extravasation in a newborn: a case report

ObjectiveExtravasation of infused drugs is not a rare problem in medical practice. Acyclovir is a vesicant and an antiviral medication commonly used for young children. In the present study, we presented a neonate with soft tissue damage due to acyclovir extravasation.Case reportA female newborn (Iranian, Asian) with gestational age 37+2 weeks and breech presentation was born by Cesarean delivery from a mother with a recent history of Herpes simplex virus (HSV) infection (Yas Women’s Hospital, Tehran, Iran). Intravenous administration of acyclovir was initiated through a peripheral catheter inserted on the dorsal side of the left hand. A few minutes after the second dose, the patient showed a diffused firm swelling, local discoloration, and induration in the dorsum of the hand. The peripheral catheter was removed immediately. Hyaluronidase was injected subcutaneously in five different regions around the catheterization site. Intermittent limb elevation and cold compression (for 10 minutes) were applied. Serial follow-ups and examinations were performed hourly to check limb inflammation, ischemia, and compartment syndrome. The limb swelling and discoloration significantly improved 4 hours after the second dose of hyaluronidase.ConclusionEarly diagnosis of acyclovir extravasation and immediate management could prevent severe complications in neonates. Further studies are needed to suggest a standard approach and treatment protocol for acyclovir extravasation.

A simple method for the determination of acyclovir concentrations in human plasma using high-performance liquid chromatography

BackgroundAcyclovir is an anti-viral medication given to treat herpes simplex and herpes zoster infection. In some severe conditions such as herpes encephalitis, acyclovir is administered intravenously. However, high acyclovir doses may cause acute kidney injury and low acyclovir dose may predispose the patient to inadequate exposure to acyclovir which could be fatal in some conditions. In such cases, the acyclovir plasma concentrations will potentially guide the diagnosis and management of the kidney injury. In this study, we provide a simple and time-efficient method for analyzing acyclovir in human plasma using high-performance liquid chromatography (HPLC).ResultsThe process starts with a single protein precipitation step by adding acetonitrile to deproteinize 300 µL of plasma. The chromatographic separation conditions consist of a mobile phase of water: methanol (97:3, v/v), a flow rate of 1 mL/min, a run time of 17 min, and a detection wavelength of 254 nm. The calibration curve was linear over the range of (0.70–60 mg/L) (r2 ˃ 0.99). The retention times of acyclovir and the internal standard were around 15 and 12 min, respectively. The intra-day and inter-day analysis of acyclovir in plasma using this method exhibited accuracy and precision of less than 7%, which lies within the acceptable range. Different greenness assessment tools confirmed that the proposed method is eco-friendly.ConclusionThe proposed method of analysis of acyclovir in the plasma using HPLC is simple, green and accurate method. This method could be applied in clinical settings where monitoring acyclovir concentrations is essential as it has wide range of the concentrations that could be detected.

Herpes Simplex Virus-1 Complicated by Postherpetic Neuralgia: A Case Report

BACKGROUND: The following case describes management of severe persistent vulvar pain from postherpetic neuralgia through a ganglion impar block. CASE REPORT: A 21-year-old female patient initially presented with genital lesions consistent with herpes simplex virus-1 (HSV-1) and antibody testing suggestive of primary HSV-1 infection. After her genital lesions resolved, she continued to have severe persistent vulvar pain and was diagnosed with postherpetic neuralgia, approximately one year after initial presentation. After unsuccessful medical management with her gynecologist and primary care physician, she was referred to a specialty pain management clinic, where a ganglion impar block was performed and provided significant pain relief. CONCLUSIONS: Genital HSV-1 is a rare cause of postherpetic neuralgia which can cause debilitating pain. Its management requires a multidisciplinary approach, including gynecology, pain management, physiatry, and if appropriate, behavioral health. KEY WORDS: Vulvar pain, postherpetic neuralgia, ganglion impar block, genital pain, case report

Management of Genital Herpes Simplex Virus Infection for the Pregnant Woman

Given the prevalence of genital herpes simplex virus infection in childbearing women and the serious consequences of genital herpes transmission to the newborn during delivery, optimal management of genital herpes during pregnancy is justified. Prevention and health promotion, continuity of care and the participation of the woman and her partner in care are key elements for optimal management of the pregnant woman with genital herpes. Appropriate management of serodiscordant couples must include screening tests for the pregnant woman with a partner who is a HSV-2 carrier, proven diagnosis and individualized prenatal preventive measures. Optimising preventive measures should bring about a reduction of genital lesions at the time of delivery and consequently reduce the number of cases of neonatal herpes and of transfers of care from midwife to physician.

Stability Indicating Method Development and Validation for Estimation of Valacyclovir in Pharmaceutical Preparation

Valacyclovir is an antiviral drug that is frequently administered to treat herpes simplex and herpes zoster infections. A simple, rapid, and accurate method for quantifying valacyclovir hydrochloride in tablet and bulk form has been developed. Two distinct analysis approaches, UV and HPLC, were developed in the present study for the evaluation of valacyclovir hydrochloride in pharmaceutical preparation. The mobile phase employed in the UV technique was Methanol:10mM KH2PO4 Buffer (50:50) for estimation of the drug at 254nm, and the (VAL) achieved was 99.45%. The method's validation was completed in accordance with ICH Q2 R1 standards, and linearity was found in the 9–45g/ml range with a regression value of 0.997% and RSD values of accuracy, precision, and robustness that were less than 2. In the HPLC method, the estimation of (VAL) was assessed on a Cosmosil C-18 (250mm4.6ID, Particle size: 5) column with Methanol:10mM KH2PO4 Buffer (50:50), 1 ml/min of flow rate, detection wavelength of 254nm, and the time of retention observed to be approximately 5.03 minutes with the assay value of 99.56%. Additionally, the HPLC technique was verified in accordance with ICH standards, and linearity was found in the 10–50g/ml range with a regression coefficient value of 0.998. Precision, accuracy, and robustness all had RSDs that were under 2%. Using Methanol:10mM KH2PO4 Buffer (50:50), the HPLC technique was also used to evaluate forced degradation at 254nm. It is clear from this study that the proposed methods for valacyclovir estimate in pharmaceutical preparation are quick, efficient, and specific. They may also be applied in routine analysis for the quantification of the drug in a dosage form.

Retinoic Acid Neutralizes the Effects of Herpes Simplex Virus Type 1-Infected Cell Protein 0 (ICP0) in Retinal Pigment Epithelial Cells.

Herpes simplex virus (HSV) infection of the cornea, uvea, and retina is the leading infectious cause of blindness worldwide. This study examined the effects of retinoic acid (RA) on the protein levels of interleukin (IL)-17A and IL-23 cytokines with known proinflammatory effects and toll-like receptor 3 (TLR3) messenger RNA (mRNA) expression in retinal pigment epithelial (ARPE-19) cells treated with HSV-1-infected cell protein 0 (ICP0). We used 3-[4.5-dimethylthiazol-2-yl]-2.5-diphenyl tetrazolium bromide assay to calculate the half maximal inhibitory concentration (IC50) doses of RA and ICP0 in ARPE-19 cells. At the end of 24 hours, protein levels of IL-17A and IL-23 were analyzed using enzyme-linked immunosorbent assay. TLR3 mRNA expression levels were also calculated using reverse transcription-polymerase chain reaction (RT-PCR). RA administration decreased IL-17A levels, which were elevated by ICP0. The IL-23 levels were similar between the ICP0-treated and control groups, but the difference was significant between the ICP0-treated group and RA+ICP0 combination. These results showed that RA can significantly increase IL-23 levels in the presence of ICP0. Although ICP0 dramatically increased TLR3 mRNA expression compared with that in the control group, the RA+ICP0 combination returned TLR3 mRNA expression to a level similar to that in the control group (P = 0.419). RA may potentially neutralize HSV-1 ICP0 negative effects in ARPE-19 cells.

Inhibitory effects of algal polysaccharide extract from Cladophora spp. against herpes simplex virus infection

Herpes simplex virus (HSV) is a causative agent of fever blister, genital herpes, and neonatal herpes. Nowadays, edible algae are recognized as health food due to high nutrition content and their many active compounds that are beneficial to health. The purpose of this study is to investigate the inhibitory effects of algal polysaccharide extract from Cladophora spp. against herpes simplex virus type 1 and type 2 on Vero cells. In this study, the structure of polysaccharide extract is presented as S=O and C–O–S of the sulfate group, as identified by the FT-IR technique. The toxicity of algal polysaccharide extract on Vero cells was determined by MTT assay. The algal extract showed low toxicity on the cells, with 50% cytotoxic concentration (CC50) value greater than 5000 µg mL−1. The inhibition of HSV infection by the algal extract was then evaluated on Vero cells using plaque reduction assay. The 50% effective concentration (EC50) values of algal extract exhibited antiviral activity against HSV-1 upon treatment before, during, and after viral adsorption with and without removal of the extract were 70.31, 15.17, > 5000 and 9.78 µg mL−1, respectively. Additionally, the EC50 values of algal extract against HSV-2 upon treatment before, during and after viral adsorption with, and without removal of the extract were 5.85, 2.57, > 5000 and 26.96 µg mL−1, respectively. Moreover, the algal extract demonstrated direct inactivation of HSV-1 and HSV-2 virions as well as inhibitory effect against HSV replication. Accordingly, algal polysaccharide extract containing sulfated polysaccharides showed strong activity against HSV. Therefore, it is proved to be useful to apply Cladophora spp. polysaccharide extract as an anti-HSV agent.

Understanding the impact of congenital infections and perinatal viral exposures on the developing brain using white matter magnetic resonance imaging: a scoping review

BackgroundMagnetic Resonance Imaging (MRI)-based imaging techniques are useful for assessing white matter (WM) structural and microstructural integrity in the context of infection and inflammation. The purpose of this scoping review was to assess the range of work on the use of WM neuroimaging approaches to understand the impact of congenital and perinatal viral infections or exposures on the developing brain.MethodsThis scoping review was conducted according to the Arksey and O’ Malley framework. A literature search was performed in Web of Science, Scopus and PubMed for primary research articles published from database conception up to January 2022. Studies evaluating the use of MRI-based WM imaging techniques in congenital and perinatal viral infections or exposures were included. Results were grouped by age and infection.ResultsA total of 826 articles were identified for screening and 28 final articles were included. Congenital and perinatal infections represented in the included studies were cytomegalovirus (CMV) infection (n = 12), human immunodeficiency virus (HIV) infection (n = 11) or exposure (n = 2) or combined (n = 2), and herpes simplex virus (HSV) infection (n = 1). The represented MRI-based WM imaging methods included structural MRI and diffusion-weighted and diffusion tensor MRI (DWI/ DTI). Regions with the most frequently reported diffusion metric group differences included the cerebellar region, corticospinal tract and association fibre WM tracts in both children with HIV infection and children who are HIV-exposed uninfected. In qualitative imaging studies, WM hyperintensities were the most frequently reported brain abnormality in children with CMV infection and children with HSV infection.ConclusionThere was evidence that WM imaging techniques can play a role as diagnostic and evaluation tools assessing the impact of congenital infections and perinatal viral exposures on the developing brain. The high sensitivity for identifying WM hyperintensities suggests structural brain MRI is a useful neurodiagnostic modality in assessing children with congenital CMV infection, while the DTI changes associated with HIV suggest metrics such as fractional anisotropy have the potential to be specific markers of subtle impairment or WM damage in neuroHIV.

Population pharmacokinetics and dose rationale for aciclovir in term and pre-term neonates with herpes.

Aciclovir is considered the first-line treatment against Herpes simplex virus (HSV) infections in new-borns and infants. As renal excretion is the major route of elimination, in renally-impaired patients, aciclovir doses are adjusted according to the degree of impairment. However, limited attention has been given to the implications of immature renal function or dysfunction due to the viral disease itself. The aim of this investigation was to characterize the pharmacokinetics of aciclovir taking into account maturation and disease processes in the neonatal population. Pharmacokinetic data obtained from 2 previously published clinical trials (n = 28) were analyzed using a nonlinear mixed effects modeling approach. Post-menstrual age (PMA) and creatinine clearance (CLCR) were assessed as descriptors of maturation and renal function. Simulation scenarios were also implemented to illustrate the use of pharmacokinetic data to extrapolate efficacy from adults. Aciclovir pharmacokinetics was described by a one-compartment model with first-order elimination. Body weight and diagnosis (systemic infection) were statistically significant covariates on the volume of distribution, whereas body weight, CLCR and PMA had a significant effect on clearance. Median clearance varied from 0.2 to 1.0 L/h in subjects with PMA <34 or ≥34 weeks, respectively. Population estimate for volume of distribution was 1.93 L with systemic infection increasing this value by almost 3-fold (2.67 times higher). A suitable model parameterization was identified, which discriminates the effects of developmental growth, maturation, and organ function. Exposure to aciclovir was found to increase with decreasing PMA and renal function (CLCR), suggesting different dosing requirement for pre-term neonates.

Optimizing deep learning-based segmentation of densely packed cells using cell surface markers

BackgroundSpatial molecular profiling depends on accurate cell segmentation. Identification and quantitation of individual cells in dense tissues, e.g. highly inflamed tissue caused by viral infection or immune reaction, remains a challenge.MethodsWe first assess the performance of 18 deep learning-based cell segmentation models, either pre-trained or trained by us using two public image sets, on a set of immunofluorescence images stained with immune cell surface markers in skin tissue obtained during human herpes simplex virus (HSV) infection. We then further train eight of these models using up to 10,000+ training instances from the current image set. Finally, we seek to improve performance by tuning parameters of the most successful method from the previous step.ResultsThe best model before fine-tuning achieves a mean Average Precision (mAP) of 0.516. Prediction performance improves substantially after training. The best model is the cyto model from Cellpose. After training, it achieves an mAP of 0.694; with further parameter tuning, the mAP reaches 0.711.ConclusionSelecting the best model among the existing approaches and further training the model with images of interest produce the most gain in prediction performance. The performance of the resulting model compares favorably to human performance. The imperfection of the final model performance can be attributed to the moderate signal-to-noise ratio in the imageset.

Impact and Occurrence of Herpesvirus and Aspergillosis Superinfection in Patients with Severe COVID-19 Pneumonia

Background: Pulmonary superinfections with Herpesviridae and Aspergillus spp. are common in severe coronavirus disease 2019 (COVID-19) pneumonia but their epidemiology and impact remain poorly understood. Methods: We conducted a retrospective observational study of 61 mechanically ventilated COVID-19 patients at Deventer Hospital’s ICU (2020–2021) who underwent bronchoalveolar lavage (BL) due to clinical deterioration. We analyzed blood and respiratory samples, treatment, and clinical outcomes. Results: Among 61 mechanically ventilated COVID-19 patients who underwent BL, 34 (55.7%) had superinfections, with 18 having COVID-19-associated pulmonary aspergillosis (CAPA), 7 having herpes simplex virus (HSV) infection, and 9 having both. Patients with HSV had later diagnoses (median 14 vs. 8 days, p = 0.014), longer mechanical ventilation (median 47 vs. 18.5 days, p = 0.015), and longer ICU stays (median 74 vs. 24 days, p = 0.021) compared to CAPA patients. At baseline, laboratory parameters and treatment (dexamethasone or tocilizumab) showed no significant association with superinfections. Mortality did not differ significantly among groups. Conclusion: In mechanically ventilated COVID-19 patients undergoing bronchoalveolar lavage, HSV reactivation occurred later in the course of illness and was associated with longer mechanical ventilation and ICU stays compared to CAPA. Baseline parameters did not predict superinfections.

Gene editing for latent herpes simplex virus infection reduces viral load and shedding in vivo

Anti-HSV therapies are only suppressive because they do not eliminate latent HSV present in ganglionic neurons, the source of recurrent disease. We have developed a potentially curative approach against HSV infection, based on gene editing using HSV-specific meganucleases delivered by adeno-associated virus (AAV) vectors. Gene editing performed with two anti-HSV-1 meganucleases delivered by a combination of AAV9, AAV-Dj/8, and AAV-Rh10 can eliminate 90% or more of latent HSV DNA in mouse models of orofacial infection, and up to 97% of latent HSV DNA in mouse models of genital infection. Using a pharmacological approach to reactivate latent HSV-1, we demonstrate that ganglionic viral load reduction leads to a significant decrease of viral shedding in treated female mice. While therapy is well tolerated, in some instances, we observe hepatotoxicity at high doses and subtle histological evidence of neuronal injury without observable neurological signs or deficits. Simplification of the regimen through use of a single serotype (AAV9) delivering single meganuclease targeting a duplicated region of the HSV genome, dose reduction, and use of a neuron-specific promoter each results in improved tolerability while retaining efficacy. These results reinforce the curative potential of gene editing for HSV disease.

Mendelian randomization study on the causal effect of herpes simplex virus infection on idiopathic pulmonary fibrosis

ABSTRACT Background Previous observational studies have shown that past infection of herpes simplex virus (HSV) is associated with idiopathic pulmonary fibrosis (IPF). The present study aims to identify the causal link between HSV infection (exposure factor) and IPF (outcome factor). Research design and methods To date, the largest publicly available genome-wide association study (GWAS) for HSV infection (1,595 cases and 211,856 controls from Finnish ancestry) and for IPF (1,028 cases and 196,986 controls from Finnish ancestry) were used to perform this two-sample Mendelian randomization (MR) study. Results We found no significant pleiotropy or heterogeneity of all selected nine HSV infection-associated genetic instrumental variants (IVs) in IPF GWAS dataset. Interestingly, we found that as HSV infection genetically increased, IPF risk increased based on an inverse-variance weighted (IVW) analysis (odds ratio [OR] = 1.280, 95% confidence interval [CI]: 1.048–1.563; p = 0.015) and weighted median (OR = 1.321, 95% CI: 1.032–1.692; p = 0.027). Conclusions Our analysis suggests a causal effect of genetically increased HSV infection on IPF risk. Thus, HSV infection may be a potential risk factor for IPF.