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.

Exposure-safety relationship for acyclovir in the treatment of neonatal herpes simplex virus disease.

BACKGROUND: Neonatal herpes simplex virus (HSV) disease has been treated with high-dose (20 mg/kg/dose) acyclovir since 1991. AIMS: Determine the safety of acyclovir in infants with neonatal HSV treated with high-dose acyclovir; examine the association between acyclovir dose and exposure with adverse events (AEs). STUDY DESIGN: We obtained demographic information and acyclovir dosing via medical records. Acyclovir exposure was calculated using an established pharmacokinetic model. SUBJECTS: Infants <120 days of age with neonatal HSV discharged from four academic children's hospitals. OUTCOME MEASURES: We identified clinical and laboratory adverse events (AEs). RESULTS AND CONCLUSIONS: We identified 49 infants with neonatal HSV treated with acyclovir; 42 infants had complete 21-day dosing information. Median mean daily dose was 59 mg/kg/day. Clinical AEs were common among all gestational and postnatal age groups. Rash was the most common clinical AE (37 %). Mild laboratory AEs occurred in 2-37 % of infants. The median maximum doses (mg/kg/day) were higher among infants with hypokalemia, elevated blood urea nitrogen, and thrombocytosis. For all other laboratory AEs, the median maximum doses for infants without events were higher or equal to the median maximum dose of infants with the AE. The odds of experiencing any clinical or laboratory AE did not differ by predicted acyclovir exposure for either area under the curve (AUC) or maximum concentration (Cmax) (odds ratio [OR] = 1.00 [0.98, 1.03] and OR = 1.01 [0.93, 1.12], respectively). Although AEs were common with high-dose acyclovir exposure, severe AEs were rare. Acyclovir exposure was not associated with AEs.

Development of Provesicular Nanodelivery System of Curcumin as a Safe and Effective Antiviral Agent: Statistical Optimization, In Vitro Characterization, and Antiviral Effectiveness.

Curcumin is a natural compound that has many medical applications. However, its low solubility and poor stability could impede its clinical applications. The present study aimed to formulate dry proniosomes to overcome these pitfalls and improve the therapeutic efficacy of Curcumin. Curcumin-loaded proniosomes were fabricated by the slurry method according to 32 factorial design using Design-Expert software to demonstrate the impact of different independent variables on entrapment efficiency (EE%) and % drug released after 12 h (Q12h). The optimized formula (F5) was selected according to the desirability criteria. F5 exhibited good flowability and appeared, after reconstitution, as spherical nanovesicles with EE% of 89.94 ± 2.31% and Q12h of 70.89 ± 1.62%. F5 demonstrated higher stability and a significant enhancement of Q12h than the corresponding niosomes. The docking study investigated the ability of Curcumin to bind effectively with the active site of DNA polymerase of Herpes simplex virus (HSV). The antiviral activity and the safety of F5 were significantly higher than Curcumin. F5 improved the safety of Acyclovir (ACV) and reduced its effective dose that produced a 100% reduction of viral plaques. Proniosomes could be promising stable carriers of Curcumin to be used as a safe and efficient antiviral agent.

Herpes reactivation after the injection of hyaluronic acid dermal filler: A case report and review of literature.

INTRODUCTION: Hyaluronic acid injections is relatively safe with little risk of complications. Although herpes reactivation after the injection of hyaluronic acid is rare, it produces quite a huge pressure and panic on patients. Quite a lot cosmetic practitioners have no awareness of preventing, diagnosing, and giving correct treatment in time due to lack of experience. PATIENT CONCERNS: A 24-year-old woman presented with erythema, crusted papules, pain and swelling on the nose after receiving the injection of hyaluronic acid. A swab of the discharge fluid was obtained for bacterial and viral culture, showing positive for herpes simplex virus. DIAGNOSIS: The patient was diagnosed as herpes reactivation after the injection of hyaluronic acid. INTERVENTIONS: The patient underwent antiviral therapy with acyclovir 400 mg, 3 times daily for seven days. OUTCOMES: After a week of antiviral treatment, the clinical signs improved. CONCLUSION: Herpes reactivation after the injection of hyaluronic acid is quite rare but needed sufficient attention of cosmetic practitioners to make the proper diagnosis, prevention and treatment.

Female patients are less satisfied with biological treatment for psoriasis and experience more side-effects than male patients: results from the prospective BioCAPTURE registry.

BACKGROUND: Female sex has been reported as a predictor for treatment discontinuation with biological therapies for psoriasis, although reasons remain unclear. It can be hypothesized that lower satisfaction with biological treatment in women might add to the lower drug survival rates. OBJECTIVES: To identify possible differences in satisfaction with biological treatment between female and male patients using the Treatment Satisfaction Questionnaire for Medication (TSQM). METHODS: Data of psoriasis patients treated with biologics were obtained from the prospective, multicentre, daily-practice BioCAPTURE registry. Longitudinal TSQM data were analysed by linear mixed models. Relevant patient characteristics were incorporated as possible confounding factors. Post hoc analysis of adverse events was performed in order to investigate differences between sexes. RESULTS: We included 315 patients with 396 corresponding treatment episodes (137 adalimumab, 90 etanercept, 137 ustekinumab, 24 secukinumab and 8 infliximab). Almost forty per cent of the patients were female. Women had significantly lower baseline PASI scores (P = 0.01). Longitudinal analyses demonstrated lower TSQM scores for 'side-effects' (P = 0.05) and 'global satisfaction' (P = 0.01) in female patients compared with male patients over 1 year of treatment. Women reported more relevant adverse events in the context of biologic treatment compared to men (rate ratio 1.79; P < 0.001), with more fungal (rate ratio 2.20; P = 0.001) and herpes simplex infections (rate ratio 3.25; P = 0.005). CONCLUSIONS: This study provides a prospective, longitudinal analysis of treatment satisfaction with biologics in female and male patients with psoriasis. Women were slightly less satisfied with treatment regarding side-effects and global satisfaction. Differences in treatment satisfaction and side-effects might add to the fact that women discontinue biological treatments more often.

Eye Complications During Dupilumab Treatment for Severe Atopic Dermatitis.

Dupilumab, the first biologic approved for treatment of atopic dermatitis, has demonstrated significant clinical effect and quality of life-enhancing capacity in clinical trials. In these, dupilumab-associated conjunctivitis where reported in a minority of patients. The present case series describe 10 patients treated with dupilumab where eye complications were very common. We have described patient characteristics, including FLG mutations, atopic history and clinical effect of dupilumab. Nine of 10 developed eye-complications, most commonly conjunctivitis (in 7/10). Other adverse events were herpes simplex virus uveitis and varicella-zoster virus meningitis. Although our case series is small, we conclude that dupilumab is an effective treatment option in severe atopic dermatitis, but that the risk of adverse events from the eyes and recurrence of herpes virus infections should be kept in mind. Close collaboration with an ophthalmologist is recommended, especially among patients with severe, long-lasting atopic dermatitis and/or previous eye disease.

IL-17A contributes to HSV1 infection-induced acute lung injury in a mouse model of pulmonary fibrosis.

BACKGROUND: Patients with idiopathic pulmonary fibrosis (IPF) often experience acute exacerbation (AE) after an episode of common cold. AIMS: To establish a mouse model of virus infection-induced AE-IPF and investigate the mechanism underlying the AE-IPF. METHODS: Herpes simplex virus 1 (HSV1) was inoculated intranasally to wild-type (WT) and IL-17A gene knockout (IL-17A-/- ) mice 21 days after intratracheal administration of bleomycin (BLM). RESULTS: HSV1 infection caused acute exacerbation in mice with BLM-induced fibrosis. Compared with the BLM+Saline mice, the mice with BLM+HSV1 showed significantly higher acute lung injury (ALI) score (P < 0.0001), lower survival rate (100% vs 21.4%, P < 0.0001), poorer lung function and higher inflammatory response representing by increased total inflammatory cells in bronchoalveolar lavage fluid (BALF) (P = 0.0323), increased proportion of Th17 cells in peripheral blood (P = 0.0004) and higher inflammatory factors in BALF. In addition, HSV1 infection increased the expression of endoplasmic reticulum stress (ERS)-related proteins in mice with BLM-induced fibrosis. The inhibition of ERS by tauroursodeoxycholic acid (TUDCA, an ERS inhibitor) significantly reduced the IL-17A levels in BALF (P = 0.0140) and TH17 cells in the peripheral blood (P = 0.0084) of mice with BLM+HSV1, suggesting that suppression of ERS may reduce TH17 response in mice with AE-IPF. Compared with WT mice with BLM+HSV1, IL-17A-/- mice with BLM+HSV1 had lower ALI score (P = 0.0119), higher survival rate (78.6% vs 21.4%, P = 0.004), improved lung function, and milder inflammatory response. CONCLUSIONS: HSV1 infection in addition to BLM-induced IPF can successfully establish AE-IPF in mice. IL-17A and ERS promote lung inflammation in AE-IPF development.

Clinical efficacy and safety of golimumab in biologically experienced and naive patients with active ulcerative colitis: A real-life experience from two Italian IBD centers.

OBJECTIVE: To evaluate the efficacy and safety of golimumab in biological naive and experienced patients with moderately to severely active ulcerative colitis (UC) treated at two Italian IBD centers. METHODS: We retrospectively reviewed our prospectively maintained UC database from March 2015 to March 2017. Patients received golimumab 200 mg at week 0, 100 mg at week 2, then 50 mg or 100 mg every 4 weeks. Follow-up was recorded at 12 and 24 weeks and in March 2017, with a median follow-up of 64 weeks. The main outcomes evaluated were clinical remission (CR) and adverse event rates. RESULTS: Of the 59 patients (44% naive and 56% experienced), CR rate was 47% at 12-week follow-up, 55% (among the 49 patients on treatment) at 24-week follow-up and 49% (among 35 patients on treatment) at the last follow-up visit. Median treatment duration was 52 weeks (interquartile range 30-64 weeks) among patients treated for >6 months. Overall, 10 (17%) patients experienced adverse events, of whom 50% discontinued treatment. The most frequent adverse events were infections. Biological naive and experienced patients did not differ in terms of CR and adverse event rates. CONCLUSIONS: Our real-life experience showed that CR decreased over time and was achieved by almost one-third of the cohort at the last follow-up visit. Golimumab showed an overall favorable safety profile and the results were not different between biological naive and experienced patients. Future research is needed to confirm our results and to identify criteria to select patients most likely to respond.

Azathioprine-induced pancytopenia with normal TPMT activity presenting with HSV oral ulcers.

A 65-year-old man with treatment-resistant psoriatic arthritis, hypertension, dyslipidaemia and benign prostatic hyperplasia (BPH) presented with herpes simplex virus (HSV) oral ulcers and a recent 15 lb weight loss due to reduced consumption. Five weeks previously, his methotrexate was tapered and he had begun taking azathioprine. The patient's thiopurine S-methyltransferase (TPMT) activity level was normal prior to starting azathioprine. He was found to have pancytopenia with normal folate levels and azathioprine was discontinued. His pancytopenia worsened, with a nadir 8 days after stopping azathioprine, before returning to normal levels. His oral ulcers improved and he was able to tolerate solid food. This case illustrates that decreased TPMT activity is not the only risk factor for pancytopenia as an adverse reaction to azathioprine. Furthermore, HSV stomatitis may be the presenting symptom of pancytopenia. The timeline of improvement in cell counts illustrated in this patient has implications for the management of suspected azathioprine-induced pancytopenia.

QUIESCENT HERPES SIMPLEX KERATITIS REACTIVATION AFTER INTRAVITREAL INJECTION OF DEXAMETHASONE IMPLANT.

PURPOSE: To report reactivation of herpes simplex virus keratitis after the injection of dexamethasone implant (Ozurdex) and to raise the awareness of this potentially vision threatening side effect. METHODS: A 90-year-old man presented with ocular pain and tearing in the left eye 3 weeks after receiving a dexamethasone implant (Ozurdex) for the treatment of macular edema associated with branch retinal vein occlusion. The patient had a history of herpes simplex virus keratitis that was quiescent for more than 30 years. RESULTS: Clinical examination of the left eye showed arborizing epithelial ulcer with terminal bulbs consistent with herpes simplex virus keratitis. CONCLUSION: Quiescent herpes simplex virus keratitis can be reactivated after dexamethasone implant (Ozurdex). Prophylactic antiviral therapy might be indicated in individuals who have a high risk of recurrent herpetic disease.

α Herpes Virus Infections Among Renal Transplant Recipients.

The α herpes viruses HSV-1, HSV-2, and VZV often reactivate in the setting of immune suppression after solid organ transplantation. Oral or genital mucocutaneous disease is the most common clinical manifestation of HSV disease while VZV manifests as varicella (or chickenpox) or reactivation herpes zoster, characterized by a diffuse rash, or a painful unilateral vesicular eruption in a dermatomal distribution, respectively. The diagnosis of HSV and VZV is primarily based on history and clinical presentation, although diagnostic tests may be necessary for atypical presentations of disease. Treatment usually involves oral or intravenous antiviral therapy, depending on severity of illness.

Real-world comparative risks of herpes virus infections in tofacitinib and biologic-treated patients with rheumatoid arthritis.

OBJECTIVE: To evaluate the risks of herpes zoster (HZ) and herpes simplex virus (HSV) infection associated with tofacitinib compared with biologic agents among patients with rheumatoid arthritis (RA). METHODS: Using health plan data from 2010 to 2014, patients with RA initiating tofacitinib or biologics with no history of HZ or HSV were identified, as were incident cases of HZ or HSV. Crude incidence rates were calculated by drug exposure. Cox proportional hazards models evaluated the adjusted association between tofacitinib and HZ, and a composite outcome of HZ or HSV. RESULTS: A total of 2526 patients initiating tofacitinib were compared with initiations of other biologics: anti-tumour necrosis factor (TNF) (n=42 850), abatacept (n=12 305), rituximab (n=5078) and tocilizumab (n=6967). Patients receiving tofacitinib were somewhat younger (mean age 55 years) versus those on other biologics, and somewhat less likely to use concomitant methotrexate (MTX) (39% vs 43%-56%, depending on drug). Crude incidence of HZ associated with tofacitinib was 3.87/100 patient-years (py). After multivariable adjustment, HZ risk was significantly elevated, HR 2.01 (95% CI 1.40 to 2.88) compared with abatacept. Rates and adjusted HRs for all other RA biologics were comparable with each other and abatacept. Older age, female sex, prednisone >7.5 mg/day, prior outpatient infection and greater number of hospitalisations were also associated with increased HZ risk. Incidence rates for the combined outcome were greatest for tofacitinib (7.61/100 py) and also significantly elevated after adjustment (HR=1.40, 95% CI 1.09 to 1.81). CONCLUSIONS: The rate of zoster associated with tofacitinib was approximately double that observed in patients using biologics.

Antimicrobial Photodynamic Therapy to treat chemotherapy-induced oral lesions: Report of three cases.

The development of Angular Cheilitis and the reactivation of Herpes Simplex Virus, could be related to a decrease in the resistance of the immune system in the infected host, being common in cancer patients receiving antineoplastic chemotherapy. The objective of the present manuscript is to report Antimicrobial Photodynamic Therapy as a treatment of infected oral lesions of patients submitted to chemotherapy.

Oral Mucositis in Pediatric Acute Lymphoblastic Leukemia Patients: Evaluation of Microbiological and Hematological Factors.

OBJECTIVE: to investigate the associations of oral microbiota, leucocytes count, neutrophil count, platelet counts and hemoglobin level, and the severity of oral mucositis in pediatric patients with acute lymphoblastic leukemia (ALL) receiving chemotherapy. MATERIALS AND METHODS: 71 prospective patients were included. Analyses of oral microbiota and blood sample were conducted on days 14 (D14) and 56 (D56) of the Brazilian GBTLI-99 treatment protocol. Herpes simplex virus (HSV) identification was performed by PCR followed by DNA sequencing analysis. Bacteria and fungi identification was obtained by standard microbiological culture tests. RESULTS: 103 episodes of mucositis occurred, being 65 at D14 and 38 at D56. Most cases positive for herpes viral DNA sequences were identified as HSV-1. At D14, we found a significant association between the severity of mucositis and presence of HSV-1 (p = 0.0347), Candida spp. (p = 0.0078), and low platelet count (p = 0.0064). At D56, we found a significant association between the severity of mucositis and the presence of HSV-1 (p = 0.0317), previous HSV-1 presence on D14 (p < 0.0001) and neutrophil count (p = 0.0211). CLINICAL RELEVANCE: the identification of risk factors for mucositis in children and adolescents may contribute to the development of new strategies for prevention and/or treatment, reducing the complications associated with this condition. CONCLUSIONS: the presence of HSV, platelet count, and Candida spp. presence at D14 of ALL induction treatment is associated with increased severity of mucositis in children and adolescents. At D56 of ALL treatment, mucositis severity was associated with neutrophil count, HSV presence, and previous presence of HSV (at D14).

Catastrophic gastrointestinal complication of systemic immunosuppression.

We present a case of acute upper gastrointestinal haemorrhage in a patient with systemic vasculitis immunosuppressed on cyclophosphamide and prednisolone. The patient presented with a diffuse haemorrhagic oesophagitis and a non-specific duodenitis. Biopsies taken from the oesophagus and duodenum demonstrated infection with herpes simplex virus (HSV) and cytomegalovirus (CMV) respectively. Viral infection of the upper gastrointestinal tract is a recognised complication of immunosuppression and HSV is one of the most common pathogens. CMV on the other hand most commonly causes a colitis or less commonly oesophagitis. CMV enteritis is rare as is the synchronous infection with two viral agents in an immunocompromised patient having being described in a few case series only. Viral infection of the gastrointestinal tract in immunocompromised patients should be treated with systemic anti-viral medication and consideration to withdrawal of the immunosuppressive therapy if possible and appropriate. The authors highlight the need for a high suspicion of viral infection in immunosuppressed patients presenting with upper gastrointestinal bleeding.

Efficacy and Safety of Anti-Interleukin-20 Monoclonal Antibody in Patients With Rheumatoid Arthritis: A Randomized Phase IIa Trial.

OBJECTIVE: Interleukin-20 (IL-20) is implicated in the pathogenesis of rheumatoid arthritis (RA). The efficacy, safety, and tolerability of NNC0109-0012, a selective anti-IL-20 recombinant human monoclonal antibody (mAb), were assessed in patients with active RA who had an inadequate response to methotrexate therapy. METHODS: Sixty-seven patients with RA were enrolled and randomized (2:1) to receive NNC0109-0012 (3 mg/kg per week, subcutaneously) or placebo in a phase IIa, double-blind, 12-week trial with a 13-week followup. The primary end point was change in the Disease Activity Score in 28 joints based on C-reactive protein level (DAS28-CRP) from baseline to week 12. RESULTS: In patients treated with NNC0109-0012, the primary end point, improvement in the DAS28-CRP at week 12, was achieved (estimated difference -0.88; P = 0.02), with significant improvement starting at week 1. A greater response was observed in seropositive patients (estimated difference -1.66; P < 0.001), which was sustained through 13 weeks of followup, whereas no improvement was noted in patients with seronegative RA. A significant proportion of patients with seropositive RA receiving NNC0109-0012, compared to those receiving placebo, achieved treatment responses according to the American College of Rheumatology 20% (ACR20) (59% versus 21%), ACR50 (48% versus 14%), and ACR70 (35% versus 0%) levels of improvement, and showed greater improvements in the Health Assessment Questionnaire disability index (P = 0.047). The most frequent adverse events reported with NNC0109-0012 were injection site reactions and infections (e.g., herpes, nasopharyngitis, respiratory, and urinary). No serious infections or discontinuations associated with NNC0109-0012 were observed. CONCLUSION: In this phase IIa trial, treatment with NNC0109-0012 (anti-IL-20 mAb) was effective in patients with seropositive RA as early as week 1, with further improvements to week 12. No safety or tolerability concerns were identified with weekly NNC0109-0012 administration.

Herpes esophagitis in the setting of immunosuppression from pemphigus vulgaris therapy.

We report a case of herpes esophagitis in a 35-year-old man with pemphigus vulgaris (PV) who was undergoing treatment with corticosteroids and mycophenolate mofetil (MMF). Pemphigus vulgaris is an autoimmune intraepithelial bullous disease resulting from pathogenic IgG antibodies toward desmoglein antigens that often requires long-term immunosuppressive therapy for control of disease symptoms. Herpes esophagitis is an ulcerative eruption caused by viral reactivation in the setting of immunosuppression. Acute odynophagia in patients undergoing systemic treatment of active PV has a broad differential and warrants prompt endoscopic evaluation.

Disseminated cutaneous herpes simplex infection in a patient with Crohn's disease under azathioprine and steroids: First case report and literature review.

Immunosuppressive treatments used in the management of Inflammatory Bowel Disease, namely steroids, thiopurines and anti-TNF drugs, raise the risk of acquiring opportunistic infections. However, most of these infections are mild and self-limited, not requiring specific therapy or suspension of the immunosuppressors. We report a case of disseminated cutaneous herpes simplex infection in a patient with Crohn's disease under steroids and azathioprine.

Total dysphagia after short course of systemic corticotherapy: herpes simplex virus esophagitis.

A 72 year-old female developed a herpetic esophagitis after 3 d of oral corticotherapy for an acute exacerbation of chronic obstructive pulmonary disease, presenting as odynophagia and total dysphagia. Biopsies were taken during a first esophagogastroduodenoscopy (EGD) and the patient was referred to the thoracic surgery service with a presumptive diagnosis of esophageal cancer. A second EGD was planned for dilatation, but by that time the stenosis was completely resolved. The biopsies taken during the first EGD revealed multiple herpetic viral inclusions and ulcerations without any dysplasia or neoplasia. In front of a severe esophageal stenosis, one must still exclude the usual differential diagnosis peptic stenosis and cancer. Visualization of endoscopic lesions can suggest the diagnosis but must be promptly confirmed by biopsy, viral culture or polymerase chain reaction. Although immune systemic effects of corticotherapy are well known and herpetic esophagitis occurs most frequently in immunocompromised individuals, this case emphasizes the importance of clinical awareness concerning short courses of corticotherapy for immunocompetent individuals. This article discusses the reactivation process of herpetic infection in this context and addresses its diagnostic and therapeutic issues.