Herpes Simplex Stomatitis Research Articles

Management of herpesvirus reactivations in patients with solid tumours and hematologic malignancies: update of the Guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society for Hematology and Medical Oncology (DGHO) on herpes simplex virus type 1, herpes simplex virus type 2, and varicella zoster virus

Clinical reactivations of herpes simplex virus or varicella zoster virus occur frequently among patients with malignancies and manifest particularly as herpes simplex stomatitis in patients with acute leukaemia treated with intensive chemotherapy and as herpes zoster in patients with lymphoma or multiple myeloma. In recent years, knowledge on reactivation rates and clinical manifestations has increased for conventional chemotherapeutics as well as for many new antineoplastic agents. This guideline summarizes current evidence on herpesvirus reactivation in patients with solid tumours and hematological malignancies not undergoing allogeneic or autologous hematopoietic stem cell transplantation or other cellular therapy including diagnostic, prophylactic, and therapeutic aspects. Particularly, strategies of risk adapted pharmacological prophylaxis and vaccination are outlined for different patient groups. This guideline updates the guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society for Hematology and Medical Oncology (DGHO) from 2015 “Antiviral prophylaxis in patients with solid tumours and haematological malignancies” focusing on herpes simplex virus and varicella zoster virus.

Case Report: Treatment Resistant Ipilimumab Related Colitis in an Elderly Metastatic Melanoma Patient

Background: Ipilimumab is a fully humanized monoclonal antibody against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). In 2010, ipilimumab became the first systemic therapy to improve the overall survival of patients with advanced melanoma in two randomized phase III clinical trials. Related to its immune-cell activating mode of action, ipilimumab therapy is associated with a spectrum of immune-related adverse events (irAEs), most commonly located at the skin and gastrointestinal tract. IrAEs are managed by withdrawal of ipilimumab and early administration of high-dose corticosteroids. Ipilimumab-related colitis, refractory to corticotherapy has been reported to respond readily to treatment with the anti-tumor-necrosis-factor monoclonal antibody infliximab. Case report: We describe a case of severe ipilimumab-related colitis in an elderly patient with metastatic melanoma, responding neither to high-dose corticosteroids, nor to infliximab, and resolving only after the washout of ipilimumab. Several complications related to immunosuppression were encountered during this period including recurrent urinary tract infections, herpes simplex stomatitis, pneumonia, oropharyngeal candidiasis, and catheter septicaemia. Conclusion: Now that immunotherapy for cancer becomes available also for the older patient, irAEs will be more frequently encountered by geriatricians. Although the treatment guidelines remain unchanged for older patients, our case demonstrates that older patients may not react easily to standard treatment. Early diagnosis of the irAEs and prompt withdrawal of ipilimumab are essential. Hence, geriatricians may have to play a crucial role for optimal management of these patients.

A Young Adult Male with Chronic Mucocutaneous Candidiasis (CMC) with Signal Transduction and Activator of Transcription 1 (STAT 1) Mutation and Progressive Multifocal Leukoencephalopathy (PML)

M O N D A Y 600 Variable Presentations of Gain of Function STAT1 Mutations within a Single Institution with Features Beyond Chronic Mucocutaneous Candidiasis Sheila M. Bina, MD, Jenni Y. Yoon, MD, Jennifer W. Leiding, MD; University of South Florida, St. Petersburg, FL. RATIONALE: Gain of function (GOF)mutations in signal transducer and activator of transcription 1 (STAT1) are a major cause of chronic mucocutaneous candidiasis (CMC). Susceptibility to viral, bacterial, fungal, and mycobacterial infections can also occur. In addition to infection susceptibility, patients with GOF-STAT1 mutations suffer from many other manifestations. METHODS: Retrospective chart reviews were performed on 5 patients with GOF-STAT1 mutations to identify specific infectious susceptibility and other immunologic manifestations. RESULTS: All 5 patients identified have mutations in the coiled-coiled or DNA binding domains of STAT1, all consistent with gain of function. Four patients have CMC, 1 has recurrent herpes simplex virus stomatitis, 1 had Mycobacterium fortuitummediastinal lymphadenitits, and 2 have recurrent sinopulmonary infections. One patient presented at 5 months of age with immunodysregulation-polyendocrinopathy-enteropathy-X-linked (IPEX) like manifestations including severe refractory diarrhea, diabetes, and failure to thrive. Successful matched unrelated bone marrow transplant was performed at 3 years of age. In addition to CMC, one patient had a giant hand granuloma caused by Trichopyton tonsurans. Other non-infectious manifestations include generalized seizures, autoimmune hemolytic anemia, recurrent thrombosis, and squamous cell carcinoma. CONCLUSIONS: In addition to CMC, these patients demonstrate broad infectious susceptibility and many other manifestations of GOF-STAT1 mutations including IPEX-like disease, vascular disease, autoimmunity, and malignancy.

Development of Herpes Simplex Virus Stomatitis during Receipt of Cidofovir Therapy

We report 3 children who, after undergoing hematopoietic stem cell transplant, developed herpes simplex virus (HSV) stomatitis while receiving weekly cidofovir as preemptive treatment for cytomegalovirus infection. All patients responded well to treatment with either acyclovir or ganciclovir. Despite the in vitro susceptibility of HSV to cidofovir, once-weekly treatment with this agent may not be adequate prophylaxis in pediatric patients.

Acyclovir To Prevent Herpes Zoster in Myeloma Patients Treated with Bortezomib.

While the major immune impairment in myeloma is humoral (hypogammaglobulinemia), cell-mediated immunity (CMI) is also impaired. CMI abnormalities include defective generation of cytotoxic T cells and impaired response to mitogens. Treatment also suppresses CMI. Reactivation of the varicella zoster virus (VZV) with development of herpes zoster (shingles) is a consequence of suppressed CMI. The pain associated with post-herpetic neuralgia can be severe, prolonged and disabling, and compromises quality of life dramatically. Because of this, it has been our long-standing policy to place all myeloma patients on indefinite prophylactic anti-viral agents once disease-specific therapy is initiated. The table below shows our standard anti-viral drug regimens for prevention of VZV reactivation.Herpes zoster prophylaxis scheduleDrugDoseCommentAcyclovir400 mg dailyThe standard regimenAcyclovir200 mg dailyIf serum creatinine >2 mg/dLValaciclovir250–500 mg dailyAlternative to acyclovirFamciclovir500 mg dailyAlternative to acyclovirThe acyclovir dose is increased to 400 mg thrice a day for a few weeks after intensive combination chemotherapy or high-dose melphalan-autotransplantation to prevent herpes simplex stomatitis. Development of VZV reactivation on this strategy has been exceptional, and the few breakthrough zoster episodes have always been associated with discontinuation of prophylaxis by the patient. Concern has been raised recently about development of zoster in myeloma patients receiving bortezomib. We undertook a retrospective review to see if zoster has been seen in myeloma patients while on acyclovir prophylaxis. The study population consisted of bortezomib-treated patients (n=125) who received all of their therapy at Northwestern over the last 3 years, and who were followed at least once a month during therapy. A detailed medication history was taken at each visit to ensure compliance. Patients who received all or part of their therapy elsewhere and were seen less frequently, a much larger population, were excluded. Patients received bortezomib either in the standard manner (days 1, 4, 8 and 11 every 21 days) or on a once-weekly schedule. The duration of bortezomib therapy was 1–164 weeks (median 16 weeks). The total duration of bortezomib therapy was 4150 weeks (80 patient-years). Except for the occasional missed dose (forgetting or running out of medication), the self-reported compliance with anti-viral prophylaxis was 100%. Not a single episode of herpes zoster was seen during this period. No adverse effects were seen that could be definitely attributed to acyclovir, valaciclovir or famciclovir. This finding was consistent with our observation of lack of VZV reactivation in myeloma patients on other regimens commonly used at our center such as pulse dexamethasone, thalidomide and combinations, lenalidomide and combinations, CDEP and DT-PACE combination chemotherapy, and high-dose melphalan with autotransplantation - as long as they are on anti-viral prophylaxis. We conclude that daily acyclovir (or a suitable alternative) is virtually universally effective at preventing herpes zoster in patients with myeloma who are on bortezomib or bortezomib-containing regimens. Despite the lack of a prospective randomized study, we suggest that long-term acyclovir prophylaxis should employed universally in myeloma patients once disease-specific therapy is started. The live-attenuated zoster vaccine (Zostavax®) is contraindicated in immunocompromised patients, and should not be used as an alternative to prevent shingles in myeloma.

Promising early outcomes with a novel, complete steroid avoidance immunosuppression protocol in pediatric renal transplantation.

Corticosteroids have been a cornerstone of immunosuppression for four decades despite their adverse side effects. Past attempts at steroid withdrawal in pediatric renal transplantation have had little success. This study tests the hypothesis that a complete steroid-free immunosuppressive protocol avoids steroid dependency for suppression of the immune response with its accompanying risk of acute rejection on steroid withdrawal. An open labeled prospective study of complete steroid avoidance immunosuppressive protocol was undertaken in 10 unsensitized pediatric recipients (ages 5-21 years; mean 14.4 years) of first renal allografts. Steroids were substituted with extended daclizumab use, in combination with tacrolimus and mycophenolate mofetil. Protocol biopsies were performed in the steroid-free group at 0, 1, 3, 6, and 12 months posttransplantation. Clinical outcomes were compared to a steroid-based group of 37 matched historical controls. Graft and patient survival was 100% in both groups. Clinical acute rejection was absent in the steroid-free group at a mean follow-up time of 9 months (range 3-13.7 months). Protocol biopsies in the steroid-free group (includes 10 patients at 3 months, 7 at 6 months, and 4 at 12 months) revealed only two instances of mild (Banff 1A) subclinical rejection (reversed by only a nominal increase in immunosuppression) and no chronic rejection. At 6 months the steroid-free group had no hypertension requiring treatment (P=0.003), no hypercholesterolemia (P=0.007), and essentially no body disfigurement (P=0.0001). Serum creatinines, Schwartz GFR, and mean delta height Z scores trended better in the steroid-free group. In the steroid-free group, one patient had cytomegalovirus disease at 1 month and three had easily treated herpes simplex stomatitis, but with no significant increase in bacterial infections or rehospitalizations over the steroid-based group. The steroid-free group was more anemic early posttransplantation (P=0.004), suggesting an early role of steroids in erythrogenesis; erythropoietin use normalized hematocrits by 6 months. Complete steroid-free immunosuppression is efficacious and safe in this selected group of children with no early clinical acute rejection episodes. This protocol avoids the morbid side effects of steroids without increasing infection, and may play a future critical role in avoiding noncompliance, although optimizing renal function and growth.

Mucocutaneous manifestations of HIV infection in 91 children born to HIV-seropositive women.

We examined 91 children under the age of 13 years with definite HIV infection born to HIV-seropositive women. The clinical spectrum of HIV infection in children younger than 13 years who are born to HIV-infected mothers was revised in 1994 into four clinical categories: category N (not symptomatic), category A (mildly symptomatic), category B (moderately symptomatic), and category C (severely symptomatic). Mucocutaneous manifestations were found in 47 (51.6%) of these children. The prevalence of mucocutaneous manifestations in categories A, B, and C were 4%, 62%, and 75%, respectively. The mucocutaneous manifestations in patients in categories B and C were significantly more common than in those category A (p < 0.001). The most common finding was oral candidiasis (36.3%). Drug rash, pruritic papular eruption, herpes zoster, cutaneous candidiasis, Penicillium marneffei infection, and herpes simplex virus stomatitis were found in 6.6%, 5.5%, 4. 4%, 3.4%, and 2. 2% of patients, respectively. All three patients who had disseminated P. marneffei infection were in category C.

An Uncommon Cause of Oral Ulcers

A 25-year-old Hispanic woman presented with painful oral ulcers, a sore throat, and dysphagia of two weeks' duration. She was treated empirically with acyclovir for presumed herpes simplex stomatitis and esophagitis and sent home. A week later, she returned with complaints of worsening sore throat, fever (as high as 38.9°C), and cough producing yellow-green sputum. She had not had chills, shortness of breath, burning on urination, or a change in bowel habits.

Serious Infectious Complications of Corticosteroid Therapy for COPD

We report seven elderly patients with COPD who developed serious infectious complications during prolonged treatment with high doses of corticosteroids. Infections included invasive pulmonary aspergillosis, Herpes simplex stomatitis and esophagitis, cytomegalovirus pneumonia, bacterial sepsis, fungemia and meningitis due to Cryptococcus neoformans. Each of the three patients who developed invasive aspergillus pneumonia died. The efficacy of prolonged therapy with high doses of corticosteroids in patients with COPD is not proven. These cases illustrate the potential for serious infections in patients with COPD treated with corticosteroids.

Herpes simplex virus and facial palsy

An 8-year-old boy developed acute herpes simplex virus stomatitis followed by transient facial palsy. The possible relationship between this virus and Bell's palsy is discussed.

Cellular and humoral immune responses to herpes simplex virus during and after primary gingivostomatitis.

A total of 17 children, aged 1 to 15 years, with gingivostomatitis were investigated to follow the development of immune parameters in those who suffered from herpes simplex virus stomatitis. Mouth swabs were obtained during the acute attack. Blood samples were collected on this occasion and again about 3 weeks later. Humoral immunity to herpes simplex virus was investigated by a complement fixation test and by an antibody-dependent cell-mediated cytotoxicity test. Cell-mediated immunity was investigated in a blast transformation assay with herpes simplex virus type 1 antigen and phytohemagglutinin. Interferon production in herpes-stimulated cultures was measured. Thirteen patients had a herpes simplex stomatitis. Twelve of these children were negative in the complement fixation test on the first serum specimen, but only five were negative in the antibody-dependent cell-mediated cytotoxicity test. These five were still febrile at the time of investigation. Blast transformation was negative at the first investigation in most children, whereas interferon was produced both in leukocyte cultures obtained during the infection and also in cultures made 3 to 4 weeks after the infection. An increase in immune parameters was seen in all patients with herpes stomatitis. From results in blast transformation and antibody-dependent cell-mediated cytotoxicity, it is seen that cell-mediated and humoral immunity can be found at the same time during recovery from this type of infection.

An outbreak of hand-foot-and-mouth disease in a dental hospital

An outbreak of hand-foot-and-mouth disease among students and staff members of a dental hospital is described. Coxsackie virus A, type 16, was isolated from the saliva of two patients but only after concentration procedures had been used. A probable explanation for this finding is offered. The clinical features are compared with those of some previous outbreaks, and the oral lesions in particular are contrasted with those found in herpes simplex stomatitis. The two conditions may be confused when clinical criteria alone are available.

The Use of Idoxuridine in the Treatment of Severe Acute Primary Herpes Simplex Stomatitis, and Pharyngitis in an Adult

The Use of Idoxuridine in the Treatment of Severe Acute Primary Herpes Simplex Stomatitis, and Pharyngitis in an Adult

Epidemic herpetic stomatitis in an orphanage nursery.

An unusual outbreak of herpes simplex stomatitis occurred in a group of 13 children 11 mo to 35 mo of age. Herpes simplex virus was isolated from eight of the ten children with clinically apparent illness. In all cases, the viruses which were isolated in HeLa cell cultures caused cytopathic effects identical to those of the proliferative strain of herpes simplex virus and characterized by rounding and clumping of cells without formation of syncytia. Serologic studies demonstrated a rise in serum-neutralizing antibodies in all eight symptomatic children whose sera were available, and no rise in the three asymptomatic children. This outbreak was characterized by its unusually high attack rate, the nature of the strain of the virus isolates, and the lack of in-apparent infection.

Erythema multiforme caused by Coxsackie B5. A possible association with epidemic pustular stomatitis of children.

In the summer of 1959 in the Boston area, there was an epidemic of a peculiar vesiculopustular of children, involving the mouth, the anterior buccal mucosa, and the vermillion border of the lips. Local pediatricians diagnosed these cases as herpangina or herpes simplex stomatitis since such cases were not uncommon in their summer practices in previous years. In this instance the peculiar clinical distribution and appearance of lesions suggested that this syndrome may have been caused by a completely different etiologic agent. Cases exhibited unusual, whitish, flattened or conical, discrete, pustular lesions, quite dramatic in appearance on the vermillon borders of the lips. Pustular lesions and shallow ulcers involved the anterior half of the buccal cavity also, with occasional rare ulceration noted more posteriorly. Lesions were noted on the hard and soft palate but only rarely on the tongue. Regional adenopathy was present with slight tenderness on palpation. The