Mucocutaneous Herpes Simplex Virus Infection Research Articles

Clinical features of atypical presentations of mucocutaneous herpes simplex virus infection observed in immunosuppressed individuals. Part I: herpetic geometric glossitis.

Herpetic geometric glossitis is a unique morphologic variant of HSV (herpes simplex virus) type 1 infection on the dorsum of the tongue that presents as an extremely painful linear central lingual fissure with a branched pattern. in the center of the tongue; there is a branched pattern of fissures that extend bilaterally from the central linear fissure. Herpetic geometric glossitis has been reported in 11 patients; 8 of these individuals were immunocompromised. Medical conditions and immunosuppressive medication treatment (7 patients) or only medical disorders (3 patients) or neither (1 patient) were present. HSV type 1 infection was diagnosed by viral culture in (7 patients), Tzanck preparation (2 patients) or clinically (2 patients). Mucocutaneous HSV infection at non-lingual locations--including the lips, labial mucosa, face and chest--were observed in 5 patients. All patients' symptoms and lesions responded to treatment with oral antiviral therapy: acyclovir (9 patients), famciclovir (1 patient) or valacyclovir (1 patient). The lingual pain and dorsal tongue fissures completely resolved completely within two to 14 days. In summary, herpetic geometric glossitis is a unique HSV type 1 infection, usually in immunocompromised patients, that occurs on the dorsal tongue and responds completely after treatment with orally administered antiviral therapy.

Clinical features of atypical presentations of mucocutaneous herpes simplex virus infection observed in immunosuppressed individuals. Part II: the knife-cut sign.

The knife-cut sign is a distinctive manifestation of herpes simplex virus (HSV) type 1 or HSV type 2 infection that has been described in at least 10 immunocompromised patients. It appears as an extremely painful linear erosion or fissure in an intertriginous area such as the body folds beneath the breast, or within the abdomen, or in the inguinal region. Also, concurrent HSV infection at other mucocutaneous sites, or viscera, or both have been observed. The patients had medical conditions (at least 9 patients) and/or immunosuppressive drug therapy (6 patients). The diagnosis of HSV infection was confirmed by viral culture (8 patients), biopsy (4 patients), direct fluorescence antibody testing (3 patients), immunohistochemistry staining (2 patients), polymerase chain reaction (2 patients), or Western blot serologic assay (1 patient). Knife-cut sign-associated HSV infection is potentially fatal; three patients died. However, clinical improvement or complete healing occurred in the patients who received oral valacyclovir (1 patient), or intravenous acyclovir (2 patients), or intravenous acyclovir followed by foscarnet (1 patient). In summary, HSV infection associated with a positive the knife-cut sign is a potentially fatal variant of HSV infection that occurs in the intertriginous areas of immunocompromised patients and usually requires intravenous antiviral therapy.

A Multicenter Assessment of the Outcomes and Toxicities of Foscarnet for Treatment of Acyclovir-Resistant Mucocutaneous Herpes Simplex in Immunocompromised Patients.

Acyclovir-resistant mucocutaneous herpes simplex virus (HSV) infection is an uncommon problem typically seen in immunocompromised hosts. Systemic treatment options are limited. The performance of foscarnet and its toxicities in this population are poorly characterized. This was a multicenter retrospective study of adults treated with foscarnet for HSV infection between January 2012 and December 2017. Relevant data were collected including demographics, baseline conditions, previous anti-HSV medications, concomitant medications, HSV outcomes, and adverse events. Acyclovir-resistant HSV infection was defined based on genotypic or phenotypic testing results; refractory infection was defined as infection not improving after 5 days of treatment-dosed antiviral therapy in those not tested for resistance. Twenty-nine patients had 31 episodes of HSV (15/18 resistant; among episodes without resistance testing, 7/10 refractory; 3 not evaluable) treated with foscarnet. All patients were immunocompromised including 19 (66%) with hematologic malignancy and 9 (31%) with HIV. Median duration of foscarnet was 16 days (range, 6-85 days). Fifteen episodes (48%) healed by the end of or after foscarnet. Median time to healing among those with resolution was 38 days (range, 9-1088 days). At least 1 adverse event during therapy was reported in 26 (84%) treatment episodes including 23 (74%) that were considered drug related. Common adverse events were electrolyte disturbance (20 [65%]) and kidney dysfunction (13 [42%]). Foscarnet was discontinued in 10 episodes (32%) due to an adverse event, including 6 due to kidney dysfunction. Among 31 episodes of HSV treated with foscarnet, only half resolved with treatment, and adverse events were common.

P76 Management of aciclovir-resistant mucocutaneous herpes simplex virus infection: a systematic review

Abstract Aciclovir resistance results in immunocompromised hosts due to long-term antiviral therapy and ongoing viral replication. Aciclovir resistance in herpes simplex virus (HSV) poses a major concern, as this can lead to chronic and recalcitrant infection that significantly impacts on the quality of life. While different treatment options exist, there are currently no standardized clinical treatment guidelines for mucocutaneous aciclovir-resistant (ACV-R) HSV infection. This systematic review seeks to identify safe and effective treatments for mucocutaneous ACV-R HSV infection. For this systematic review, PubMed/MEDLINE and Embase were searched in September 2022 for all articles published between 1 January 1980 and 1 September 2022. Studies were included if they described the use of a medication for the treatment of mucocutaneous ACV-R HSV infection. From the initial search that yielded 1066 studies, 86 met the inclusion criteria and were selected. Of the 86 studies, 6 were clinical trials and 80 were case reports/series. A total of 318 patients were included in our review. Foscarnet [intravenous (IV) and topical] was studied in 5 clinical trials and 25 case reports/series, leading to complete response in most patients, with adverse effects including renal toxicity and electrolyte abnormalities. Vidarabine (IV) was found to be inferior to foscarnet in a clinical trial and reported in two case reports. Common side-effects included nausea, anaemia and renal impairment. Trifluridine (topical) was studied in a clinical trial and a case report, showing complete response in some patients. Cidofovir (IV, topical, intralesional) was studied in 21 case reports/series, showing complete response in most patients, with renal impairment as the most common adverse effect. Imiquimod (topical) was studied in eight case reports/series, showing complete response and no side-effects. Pritelivir (oral) was reported in two case reports/series, showing complete response and no side-effects. Combination treatment was reported in 10 case reports/series with variable clinical response. Our review also identified reports of less widely used treatments. These include artesunate, zidovudine, varicella-zoster virus vaccine, leflunomide and surgical excision, which achieved variable response rates but have not been widely studied. While foscarnet and cidofovir have the most robust evidence, IV administration of these agents is associated with significant side-effects and may be limiting. Intralesional and topical formulations of cidofovir, trifluridine and imiquimod are alternative options appropriate for outpatient management. Pritelivir is a novel and promising treatment of mucocutaneous ACV-R HSV infection.

BI03 (P76) Management of aciclovir-resistant mucocutaneous herpes simplex virus infection: a systematic review

Abstract Aciclovir resistance results in immunocompromised hosts due to long-term antiviral therapy and ongoing viral replication. Aciclovir resistance in herpes simplex virus (HSV) poses a major concern, as this can lead to chronic and recalcitrant infection that significantly impacts on quality of life. While different treatment options exist, there are currently no standardized clinical treatment guidelines for mucocutaneous aciclovir-resistant (ACV-R) HSV infection. This systematic review seeks to identify safe and effective treatments for mucocutaneous ACV-R HSV infection. For this systematic review, PubMed/MEDLINE and Embase were searched in September 2022 for all articles published between 1 January 1980 and 1 September 2022. Studies were included if they described the use of medications for the treatment of mucocutaneous ACV-R HSV infection. From the initial search that yielded 1066 studies, 86 met the inclusion criteria and were selected. Of the 86 studies, six were clinical trials and 80 were case reports/series. A total of 318 patients were included in our review. Foscarnet [intravenous (IV) and topical] was studied in five clinical trials and 25 case reports/series, leading to complete response in most patients, with adverse effects including renal toxicity and electrolyte abnormalities. Vidarabine (IV) was found to be inferior to foscarnet in a clinical trial and reported in two case reports. Common side-effects included nausea, anaemia and renal impairment. Trifluridine (topical) was studied in a clinical trial and a case report, showing complete response in some patients. Cidofovir (IV, topical, intralesional) was studied in 21 case reports/series, showing complete response in most patients, with renal impairment as the most common adverse effect. Imiquimod (topical) was studied in eight case reports/series, showing complete response and no side-effects. Pritelivir (oral) was reported in two case reports/series, showing complete response and no side-effects. Combination treatment was reported in 10 case reports/series with variable clinical response. Our review also identified reports of less widely used treatments. These include artesunate, zidovudine, varicella-zoster virus vaccine, leflunomide and surgical excision, which achieved variable response rates but have not been widely studied. While foscarnet and cidofovir have the most robust evidence, IV administration of these agents is associated with significant side-effects and may be limiting. Intralesional and topical formulations of cidofovir, trifluridine and imiquimod are alternative options appropriate for outpatient management. Pritelivir is a novel and promising treatment of mucocutaneous ACV-R HSV infection.

Use of pritelivir in refractory aciclovir-resistant herpes simplex virus type 2

Recurrence of mucocutaneous herpes simplex virus (HSV) infections is common in immunosuppressed patients. Thymidine kinase mutations conferring resistance to the antiviral agent aciclovir have been observed in such patients. Recommended second-line therapeutic agents against HSV are associated with significant side effects contributing to disease burden. We present a case of aciclovir-resistant herpes simplex virus 2 (HSV-2) in an immunosuppressed (HIV negative) allogenic peripheral blood stem cell transplant (SCT) recipient which was refractory to second-line therapy. Compassionate acquisition of the novel oral helicase-primase inhibitor pritelivir provided both symptomatic and virological control for the duration of its use. We believe this to be the first clinical use of this therapeutic agent in the United Kingdom.

T-cell Responses to HSV-1 in Persons Who Have Survived Childhood Herpes Simplex Encephalitis.

Herpes simplex encephalitis (HSE) after primary herpes simplex virus (HSV)-1 infection can occur in children due to inborn errors of cell-intrinsic immunity in the central nervous system. Paradoxically, symptomatic mucocutaneous HSV-1 recurrences are rare survivors of childhood HSE. T-cell-acquired immunity is thought to be involved in control of recurrent mucocutaneous HSV infection. We thus tested HSV-1-specific immunity in HSE survivors. We obtained serum and peripheral blood mononuclear cells (PBMCs) from participants a median of 13.5 years after HSE. HSV-1 and HSV-2 IgG was detected by type-specific immunoblot. PBMCs from subjects passing quality control criteria were tested using enzyme-linked immunospot assay for CD4 interferon-γ responses with an HSV-1 lysate and for CD8 responses using pooled synthetic HSV-1 peptide CD8 T-cell epitopes. Healthy adult PBMCs were used to standardize assays and as comparators. All participants were HSV-1 seropositive. Most (23/24) HSE survivors had human leukocyte antigen class I types matching the human leukocyte antigen restriction of the pooled peptides. We detected HSV-specific CD8 T-cell responses in 14 of 24 (58%) HSE survivors and in 9 of 9 healthy HSV-1 seropositive adults. HSV-specific CD4 T-cell responses were present in all 5 HSE subjects tested and in 8 of 9 healthy adults. Response magnitudes were overlapping between subject groups. The defects in cell-intrinsic immunity leading to failure to control primary central nervous system HSV-1 infection do not preclude the acquisition of specific immunity or the control of recurrent mucocutaneous HSV infections. The rarity and lack of severe or recurrent mucocutaneous HSV infection in survivors of childhood HSE corresponds with intact adaptive T-cell immunity.

Should a hospitalized child receive empiric treatment with acyclovir?

BackgroundHerpes simplex encephalitis is associated with substantial morbidity and mortality and may be related to timely diagnosis and treatment. While awaiting the results of testing, hospitalization and empiric treatment with acyclovir is recommended, though the direct and indirect costs associated with this management are substantial. We sought to examine children hospitalized for possible herpes simplex encephalitis, following clinical and laboratory assessment in the emergency department, and empiric treatment with acyclovir, in order to describe the proportion receiving a complete course of treatment; and to identify the clinical variables which are associated with receiving a complete course, as compared with an incomplete course of acyclovir.MethodsHospitalized children prescribed acyclovir were included in this case control study. Clinical, laboratory and diagnostic variables were abstracted for children prescribed a complete (≥ 14 days) or an incomplete course (<14 days) of acyclovir. Odds ratios and 95% confidence intervals were calculated.Results289 children met eligibility criteria, 30 (10%) received a complete course and 259 (90%) received an incomplete course. A history of mucocutaneous herpes simplex virus infection (p < 0.01), Glasgow Coma Scale ≤ 13 (p = 0.02), focal neurologic findings (p = 0.001) and elevated cerebrospinal fluid white blood cell count (p = 0.05) were associated with a complete course of acyclovir.ConclusionsMany children did not complete a full course of therapy. Unnecessary testing and treatment is burdensome to families and the health care system. Possible predictive variables include abnormal Glascow Coma Scale, focal neurologic findings and cerebrospinal fluid pleocytosis.

Management of resistant mucocutaneous herpes simplex infections in AIDS patients: a clinical and virological challenge

The use of highly active antiretroviral therapy (HAART) has been associated with a marked decrease in the prevalence of opportunistic infections in HIV-infected patients. However, chronic mucocutaneous herpes simplex virus (HSV) infection remains a difficult clinical challenge. The aim of the study was to optimize the diagnosis and follow-up of chronic HSV-2 infection in HIV-infected patients and to correlate clinical data with CD4 cell count, in vitro HSV virological resistance and histology. A retrospective case series was collected from a specialist out-patient clinic providing consultations to patients with infectious skin diseases. Clinical, biological, virological and histological data were analysed. Seven HIV-infected patients with genital and perianal herpes simplex infection were followed over 10 years. Ulcerative and pseudo-tumoral forms were observed. Lesions occurred at various stages of immune suppression (CD4 counts from 1 to 449 cells/μL). Clinical resistance to conventional anti-herpetic drugs was correlated with the in vitro resistance of HSV in 70% of cases. Chronic mucocutaneous HSV infection in AIDS patients remains a rare but regularly observed infection in very immunosuppressed patients or those with unstable immunity during HAART. Virological results obtained from mucocutaneous samples were in most cases found to be correlated with clinical evolution and should therefore be used in making decisions on treatment. Despite efficient antiviral therapy, mucocutaneous healing is slow in the majority of cases.

Direct immunofluorescence assay compared to cell culture for the diagnosis of mucocutaneous herpes simplex virus infections in children

Background Direct immunofluorescence assay (DFA) is commonly used for the rapid identification of herpes simplex virus (HSV) infection in mucocutaneous lesions, yet little is known about its diagnostic accuracy. Objective To determine the diagnostic yield and accuracy of HSV DFA for the diagnosis of mucocutaneous HSV infection in pediatric patients. Study design Retrospective cross-sectional study of all patients who underwent HSV DFA testing by the Texas Children's Hospital Diagnostic Virology between January 1, 1995 and December 31, 2005. HSV DFA sensitivity, specificity, positive likelihood ratio (LRs), and negative LRs were estimated using viral culture as the reference standard. Results 659 specimens were submitted for HSV DFA with concurrent viral cultures. Viral cultures were positive for HSV type 1 in 158 (24%) and HSV type 2 in 2 (0.3%). There were 433 different patients with a median age of 8.6 years. Types of lesions were as follows: 50% ulcerative, 26% vesicular, 8% erythema or purpura, 5% pustular, and 11% missing. Of the 659 specimens submitted for HSV DFA, 160 (24%) were inconclusive due to inadequate cells. Of the 499 adequate specimens, overall HSV DFA test accuracy was: sensitivity 61%, specificity 99%, LR positive 40, and LR negative 0.39. Conclusions A quarter of specimens submitted for HSV DFA testing are not adequate for DFA testing. When HSV DFA can be performed, it is specific, but not sensitive, for the identification of mucocutaneous HSV infection in children.

Disseminated mucocutaneous herpes simplex virus infection in an immunocompetent woman

Disseminated mucocutaneous herpes simplex virus (HSV) infection in an immunocompetent person is quite rare. A 19-year-old healthy Japanese woman presented with painful, umbilicated vesicles and pustules on her genital region, both nipples and on the forearm 10 days after the last sexual contact with her partner who had cold sore at that time. Tzanck test and biopsy confirmed the diagnosis of disseminated mucocutaneous HSV infection. She did not have any visceral HSV disease. Skin lesions improved after treatment with acyclovir and erythromycin for seven days. We propose that like herpes gladiatorum, HSV dissemination in this case was acquired by close body contact.

The Clinical Spectrum of Herpes Simplex Viremia

The vast majority of herpes simplex virus (HSV) infections in adults are relatively benign in their clinical manifestations. However, this ubiquitous virus clearly produces a diverse spectrum of disease. Although mucocutaneous HSV infection and reactivation can be associated with more generalized symptoms, the presence of viremia had previously been considered a rare occurrence. In the mid-1900s, HSV was isolated from the blood of an immunocompetent child with herpetic rhinitis [1], signaling the possibility of more widespread infection in clinically benign disease. Subsequently, though, sensitive HSV culture techniques were unable to identify viremia in immunocompetent pediatric patients with clinical HSV infection [2]; studies of blood cultures for HSV in immunocompetent adults have not been published. More recently, highly sensitive polymerase chain reaction (PCR) assays have altered our understanding of the natural history of HSV infection. HSV DNA has been found in the blood in 34% of children with primary gingivostomatitis [3], in 24% of adults with primary genital

Herpes Simplex Virus (HSV)-1 and -2, and Varicella Zoster Virus (VZV)

Herpes Simplex Virus (HSV)-1 and -2, and Varicella Zoster Virus (VZV)

Herpes Simplex Virus in Children.

Herpes simplex virus (HSV) infections are ubiquitous. Children are infected with HSV resulting in totally asymptomatic acquisition to life-threatening disease. Therapy of HSV diseases of children can be considered according to severity and time of acquisition. Neonatal herpes simplex virus infections take one of three forms--disease localized to skin, eye, or mouth (SEM), encephalitis, or multiorgan disseminated disease. Treatment consists of intravenous (IV) administration of acyclovir. Supportive care for patients with life-threatening disease is an integral component of patient management. Mucocutaneous HSV infections in the immunocompromised host can be treated with either intravenous acyclovir or one of the orally bioavailable antiviral therapies. For hospitalized patients, therapy consists of IV acyclovir at 5 mg/kg every 8 hours for 7 to 14 days. For ambulatory patients, therapy is tailored according to age. For children less than 12 years of age, oral acyclovir is administered at a dosage of 20 mg/kg every eight hours. Although no controlled studies have been performed with valaciclovir or famciclovir, the pharmacokinetics of these medications would suggest superiority over acyclovir. Dosage recommendations have not been established for young children. For postpubertal children, dosage should mirror that of adults. Valaciclovir is administered at 500 mg twice daily. Famciclovir is administered at 125 mg three times daily. Herpes simplex keratoconjunctivitis is treated with topical triflurothymidine. Two drops are applied to the infected eye five times daily until resolved. Recurrences are managed in a similar manner. Some physicians administer oral acyclovir at the doses noted above in order to prevent frequent recurrences. Genital HSV infections can be treated with acyclovir, valaciclovir, or famciclovir. Episodic treatment of recurrent episodes is usually not necessary in childhood. Importantly, all data on the use of these compounds for these conditions have been generated in adults. Physician judgment is required for the management of recurrent herpes labialis, erythema multiforme, and herpes gladitorum. No controlled studies have been performed in children, although experience with acyclovir, valaciclovir, and famciclovir have resulted in their use.

Current Treatments of Muco-Cutaneous Herpes Simplex Virus Infections

Current Treatments of Muco-Cutaneous Herpes Simplex Virus Infections

Survival by AIDS defining condition in rural Uganda

Objectives: To report the initial AIDS defining conditions, CD4 lymphocyte counts around the time of AIDS diagnosis, and survival by AIDS defining condition in a population based cohort in rural...

A risk-benefit evaluation of aciclovir for the treatment and prophylaxis of herpes simplex virus infections.

The objective of this article is to review and evaluate risks and benefits associated with the use of acyclovir in the treatment and prophylaxis of common manifestations of herpes simplex virus (HSV) infections in immunocompetent and immunocompromised patients. Information was found through a MEDLINE search using keywords: herpes simplex virus, genital herpes, herpes labialis, acyclovir and acyclovir. Selected articles were randomised, double-blind, placebo-controlled, clinical trials. 30 such trials involving 3364 persons were evaluated. All articles were reviewed by the authors and the data were extracted and summarised. In both immunocompetent and immunocompromised hosts, acyclovir therapy demonstrated a high degree of clinical efficacy. None of the studies reported statistically significant differences between acyclovir and placebo for mild or major adverse events. This evaluation found that acyclovir is both effective and well tolerated for treatment and prophylaxis of genital, oral and mucocutaneous HSV infections in immunocompetent and immunocompromised patients. In most clinical scenarios. the benefit of acyclovir exceeded any risks by a comfortable margin. The availability of acyclovir as a generic preparation further improves the benefit to cost ratio.

The prognostic value of the World Health Organisation staging system for HIV infection and disease in rural Uganda.

To assess whether the WHO staging classification for HIV provides prognostically valuable and applicable information in rural Uganda. Data were obtained from a population-based cohort of 232 HIV-infected individuals. Clinical information was obtained using a detailed questionnaire and ascertained by physical examination. Participants were seen routinely every 3 months and when they were sick. A computer algorithm based on clinical history, examination and laboratory findings was used to stage HIV-positive participants at each routine visit. Kaplan-Meier survival estimates and the Cox proportional hazard model were used to assess the prognostic strength of the clinical and laboratory categories of the system. An attendance rate of 81% and 799 person-years of follow-up were achieved. Survival probability estimates at 6 years from being seen in clinical stages 1, 2, 3 and 4 were 63, 46, 24 and 6% respectively. When staging was revised to incorporate lymphocyte categories, the survival probabilities were 73, 62, 39 and 6% respectively. Unexplained prolonged fever and severe bacterial infection had survival probabilities closer to stage 2 conditions, mucocutaneous herpes simplex virus infection for more than 1 month and crytosporidiosis with diarrhoea for more than 1 month closer to stage 3 and oral candidiasis closer to stage 4 conditions. Even without the laboratory markers, the clinical category of the WHO staging system is useful for predicting survival in individuals with HIV disease. This is important for areas with limited access to laboratory markers. A simple rearrangement of a few clinical conditions could improve the prognostic significance of the WHO system.

Clearance of HSV-2 from recurrent genital lesions correlates with infiltration of HSV-specific cytotoxic T lymphocytes.

The mechanisms involved in host clearance of symptomatic mucocutaneous herpes simplex virus (HSV) infection are unclear. We studied the functional properties of bulk cultures of skin-infiltrating lymphocytes from normal skin and serial biopsies of recurrent genital HSV-2 lesions, and compared HSV-specific and NK responses with viral clearance. HSV-specific CD4+ or CD8+ T cells were rarely detected in lymphocytes cultured from normal skin. The total lymphocyte count and HSV-specific and NK-like effector cell activities were markedly higher in cultures derived from lesional skin. HSV-specific CD4+ proliferative responses and NK-like cytotoxic responses were present at all stages of herpetic lesions, including biopsies early in the disease course. In contrast, cytotoxic T lymphocyte activity was generally low among cells derived from early culture-positive lesions, and increased during lesion evolution. Viral clearance from the lesion site was associated with a high level of local cytolytic activity towards HSV-infected cells. The phenotypes of cells with HSV-specific cytotoxic responses varied between patients, having CD4+ and CD8+ components. Immunotherapeutic approaches to HSV should be directed at improving in vivo cytolytic activity to HSV.

Comparison of Virus Culture and the Polymerase Chain Reaction for Diagnosis of Mucocutaneous Herpes Simplex Virus Infection

The diagnosis of mucocutaneous herpes simplex virus (HSV) is hampered by suboptimal sensitivity of virus culture and atypical clinical morphology. To compare the diagnostic usefulness of the polymerase chain reaction (PCR) and virus culture. Consecutive samples from 246 patients at an urban sexually transmitted diseases clinic were tested for HSV by both PCR and virus culture. Only 59% of HSV-positive samples were correctly diagnosed by the clinician; 11% had an atypical appearance. HSV-positive lesions were more often vesiculoulcerative or crusted than HSV-negative lesions, and of shorter median duration. Thirty-one samples were PCR positive and virus culture negative; these were often from crusted or older lesions. However, PCR was negative in 27 instances in which HSV was diagnosed clinically, of which 2 were vesicular and 15 ulcerative. HSV PCR is more rapid and sensitive than virus culture for diagnosis of mucocutaneous lesions. The data suggesting that PCR may be suboptimally sensitive need to be further investigated.