Chronic oral herpes simplex virus infection in immunocompromised patients

Recurrent herpes simplex virus infection is usually benign and self-limiting, but in immunosuppressed patients it can be a chronic destructive process. Eight patients with chronic aggressive herpes simplex virus infection of the oral mucosa are described. All cases occurred in immunocompromised patients. The distinctive clinical presentation of the oral lesions, the diagnosis, and treatment are discussed.     

The deep mycoses in HIV infection

The deep mycoses are uncommon infections, usually acquired from the inhalation or ingestion of fungal spores, sometimes from the soil in areas of endemicity, such as in the Americas and south-east Asia, or from decaying vegetable matter. They are also seen in immunocompromised persons and, increasingly, in HIV-infected persons. Respiratory involvement is frequent, with granuloma formation, and mucocutaneous involvement may be seen. Oral lesions of the deep mycoses are typically chronic but non-specific, though nodular or ulcerative appearances are common. Person-to-person transmission is rare. In HIV disease, the most common orofacial involvement of deep mycoses has been in histoplasmosis, cryptococcosis, aspergillosis and zygomycosis. Diagnosis is usually confirmed by lesional biopsy although culture may also be valuable. Treatment is with amphotericin or an azole.     

A Case Series: Herpes Simplex Virus as an Occupational Hazard

ABSTRACT

Statement of the Problem: Herpes labialis infections are common and present a serious risk to the dental team. Purpose of the Study: The purpose is to make dentists aware of the risks involved with treatment of patients with active herpes labialis. In addition, evidence‐based risk‐management strategies are presented. Methods and Materials: The incidence and natural history of herpes simplex virus type 1 (HSV‐1) are reviewed. Four previously unreported case histories are presented to illustrate the impact common sequelae of HSV‐1 can have on the dental team. The differences between HSV‐1 and the blood‐borne diseases which are the focus of universal precautions are discussed. In particular, the highly contagious, highly transmissible nature of HSV‐1 and its transmission through aerosols are highlighted. Finally, the need to include protection against aerosols in the profession's understanding of universal precautions is noted. Results: The authors suggest limiting the treatment of patients with active lesions to urgent care only, and treating active HSV‐1 lesions to reduce time of healing. For four common clinical situations involving HSV‐1 infections, evidence‐based methods for protecting the dental team and the patient from cross‐contamination are also presented. Conclusion: While it is clear that the treatment of patients with active herpes labialis lesions increases risk of cross‐infection, there are good protocols for controlling this risk.

CLINICAL SIGNIFICANCE

By bringing common vectors of cross‐infection to light and providing evidence‐based protocols for preventing them, this article provides practitioners with positive steps that can be taken for controlling the risk of spreading herpes infections to the dental team. (J Esthet Restor Dent 24:61–67, 2012)     

Mucosal disease series. Number IV. Erythema multiforme

Erythema multiforme (EM) is an acute mucocutaneous hypersensitivity reaction characterised by a skin eruption, with or without oral or other mucous membrane lesions. Occasionally EM may involve the mouth alone. EM has been classified into a number of different variants based on the degree of mucosal involvement and the nature and distribution of the skin lesions. EM minor typically affects no more than one mucosa, is the most common form and may be associated with symmetrical target lesions on the extremities. EM major is more severe, typically involving two or more mucous membranes with more variable skin involvement - which is used to distinguish it from Stevens-Johnson syndrome (SJS), where there is extensive skin involvement and significant morbidity and a mortality rate of 5-15%. Both EM major and SJS can involve internal organs and typically are associated with systemic symptoms. Toxic epidermal necrolysis (TEN) may be a severe manifestation of EM, but some experts regard it as a discrete disease. EM can be triggered by a number of factors, but the best documented is preceding infection with herpes simplex virus (HSV), the lesions resulting from a cell mediated immune reaction triggered by HSV-DNA. SJS and TEN are usually initiated by drugs, and the tissue damage is mediated by soluble factors including Fas and FasL.     

Multiple oral and labial ulcers in an immunocompromised patient

Herpes simplex virus infections in immunocompromised individuals have clinical features that are often quite different from primary and secondary HSV infections in otherwise healthy people. These infections should be recognized early and treated promptly to prevent progression of the lesions and the possible systemic dissemination of the virus. Cytological and biopsy examination frequently discloses changes characteristic of HSV-1, HSV-2, or Varicella-zoster virus. To ensure the most precise diagnosis, however, these examinations should be complemented by viral isolation and serological studies.     

The incidence of oral herpes simplex virus infection in patients undergoing cancer chemotherapy

Oral lesions in twenty-nine immunocompromised patients were evaluated for the incidence of herpes simplex virus (HSV) infections during either cancer chemotherapy or cancer chemotherapy plus bone marrow transplantation (BMT). Patients' HSV antibody titers were not determined, and positive diagnoses were based solely on the results of viral cultures. Fourteen patients (48%) were found to have herpetic infections, which is comparable with incidence rates of 50% to 90% in antibody-positive patients and 40% to 50% in mixed antibody populations reported in the medical literature. However, this finding is in conflict with the 10.7% to 15.1% incidence rate cited in the dental literature for patients undergoing cancer chemotherapy. This underestimation is believed to reflect insensitivity in the criteria used for diagnosis in these studies.     

A long-term prospective clinical study of orofacial herpes simplex virus infection in acute leukemia

Orofacial mucocutaneous infections resulting from herpes simplex virus (HSV) were detected in 40% of patients with acute leukemia. Of the 34 separate episodes, oral mucosal sites were involved in 22 cases. Evidence to support dissemination of HSV was found in 3 patients on 4 separate occasions. The relationship of neutrophil levels to the onset and resolution of lesions is examined. The value of acyclovir for treatment of these HSV-induced lesions is reported, and the question of administering this agent for routine prophylaxis against HSV in these patients is addressed.     

Pyogenic granuloma on the upper lip: an unusual location

Pyogenic granuloma (PG) is a benign non-neoplastic mucocutaneous lesion. It is a reactional response to constant minor trauma and might be related to hormonal changes. In the mouth, PG is manifested as a sessile or pedunculated, resilient, erythematous, exophytic and painful papule or nodule with a smooth or lobulated surface that bleeds easily. PG preferentially affects the gingiva, but may also occur on the lips, tongue, oral mucosa and palate. The most common treatment is surgical excision. This paper describes a mucocutaneous PG on the upper lip, analyzing the clinical characteristics and discussing the features that distinguish this lesion from other similar oral mucosa lesions. The diagnosis of oral lesions is complex and leads the dentist to consider distinct lesions with different diagnostic methods. This case report with a 4 year-follow-up calls the attention to the uncommon mucocutaneous labial location of PG and to the fact that surgical excision is the safest method for diagnosis and treatment of PG of the lip, even when involving the mucosa and skin.     

Recurrent oral ulceration: Etiology,classification, management,and diagnostic algorithm

Recurrent oral ulcerations are manifestations of a heterogeneous set of both general and more‐or‐less specific oral diseases due to numerous potential etiologies, including, but not limited to, infections, medications, autoimmune disease, and other systemic disease. This review discusses the pathogenesis, clinical presentation, diagnosis, and management of the common causes of recurrent oral ulceration. The following types/etiologies of recurrent oral ulceration are covered: traumatic ulceration, chemical ulceration, recurrent aphthous stomatitis, medication‐related ulceration, infectious ulceration, mucocutaneous disease, and autoimmune/systemic disease. A diagnostic algorithm for recurrent oral ulceration is also presented.     

Paraneoplastic pemphigus: a review of the literature

Paraneoplastic pemphigus is a relatively rare but highly significant acquired mucocutaneous disorder. The condition typically presents in patients with previously diagnosed lymphoreticular disease, primarily malignancies (non-Hodgkin's lymphoma; chronic lymphocytic leukemia). Multiple sites of involvement are common, with the skin affected by a polymorphous eruption that includes lichenoid plaques as well as bullae. The oral lesions occur in all cases and present as painful widespread shallow ulcers with hemorrhagic crusting of the lips. Conjunctival involvement is also seen and may result in scarring. Pulmonary lesions are an ominous sign. Histopathologically, intraepithelial and subepithelial clefting associated with interface dermatitis are seen. A variety of autoantibodies directed against desmoplakins and desmogleins can be identified with immunoprecipitation studies. Treatment with immunosuppressive agents may result in some resolution of the disease, but the prognosis for paraneoplastic pemphigus is considered to be poor.     

Herpetic gingivostomatitis in otherwise healthy adolescents and young adults

The purpose of this study was to review and analyze the records of herpes simplex infections from a specialist Oral Medicine clinic in Iceland, to investigate the clinical impression that the age of patients experiencing initial infection with this virus was higher than expected and that the character of the clinical picture of the disease had changed. Records of patients with herpes infections attending the Oral Medicine clinic covering a 3-year period were examined and the clinical and virological data analyzed. Diagnosis was based on clinical appearance, history, and viral identification with culture or detection of viral DNA by means of the polymerase chain reaction. Records of 60 patients (34 female) were included in the study (mean age, 23.1 years; range, 2 68 years). No patients were known or suspected to be positive for human immunodeficiency virus, none was known to be immunocompromised, and 38 patients (mean age, 16.6 years; 21 female) were diagnosed as having primary herpetic gingivostomatitis. Eighteen patients (mean age, 36.2 years; 11 female) had lesions of recurrent herpes simplex infection present on the oral mucosa. Primary infection with herpes simplex virus was more common in young adults than had been expected. Recurrent infections appeared on the oral mucosal even in otherwise healthy patients, and the clinical course of these infections in this age group sometimes followed a more severe course than that seen in young children.     

PL7Oral viral infections that could be transmitted oro‐genitally

Orogenital transmission has been suggested for several viruses, e.g. herpes simplex virus‐1 and ‐2 (HS‐1 and HSV‐2), Epstein‐Barr virus (EBV), cytomegalovirus (CMV), human herpesvirus‐8 (HHV‐8), human papillomavirus (HPV) and HIV. Most studies have focused on HIV, HSV and HPV. Unprotected orogenital contact, especially receptive oral intercourse, is associated with greater risk of HIV transmission than previously thought. Factors potentially associated with increased risk of HIV transmission through oral sex include poor oral health, the salivary anti‐HIV properties such as peroxidases and thrombospondin‐1, the local and systemic immunological responses, concomitant sexually transmitted infections, ejaculation in the mouth, local mucosal integrity, and the level of infectious HIV present at the oral mucosa. The probability of per act transmission in oral intercourse with ejaculation is 0.04%. HSV‐2 has been regarded as a sexually transmitted virus while HSV‐1 is causing primary herpetic gingivo‐stomatitis, muco‐cutaneous oro‐facial disease and ocular disease. Also HSV‐2 might be detected occasionally in oro‐facial area. Recent data on young women with a primary genital infection indicate that HSV‐1 is much more frequent than HSV‐2. Oro‐genital route of transmission is more common than expected in genital HSV‐1 infections. EBV is a tumorigenic herpes virus that is carried as a persistent infection by more than 90% of adults. Most persistently infected people produce EBV in their saliva, and transmission is through close contact. There is a significant association between sexual intercourse and EBV seropositivity, increasing with numbers of sex partners. Because EBV has been found in genital secretions from healthy seropositive men and women, direct spread of virus during sexual intercourse is possible. Today, 106 HPV types have been sequenced of which almost 40 have been detected also in oral mucosa, causing benign epithelial lesions (papillomas, condylomas, warts and focal epithelial hyperplasia, or FEH). Recent meta‐analyses of the case‐control studies have confirmed HPV as an independent risk factor for oral SCC with odds ratios (OR) 3.7 to 5.4. HPV16 is the overwhelmingly most frequent type. HPV has been regarded as a sexually transmitted disease but this view is challenged by frequent detection of HPV in children. Unlike in genital tract, natural history of oral HPV infection is poorly studied. As part of the Finnish HPV Family Study we evaluated natural history of oral HPV in within family members. The detection rate of HR HPVs varied from 15% to 27%. Our results indicate that natural history of HPV infection in oral mucosa mimics that of genital HPV infections. Oral sex had no association to oral HPV infection, but a persistent oral HPV infection of the spouse increased the risk of persistent oral HPV infection in the other spouse 10‐fold.     

Oral presentation of histoplasmosis in an immunocompetent patient: a diagnostic challenge

Histoplasmosis is a rare systemic fungal infection, primarily affecting the pulmonary system. Oral lesions are usually a manifestation of the disseminated form of the disease and most frequently observed in severely immunocompromised patients, such as those with advanced human immunodeficiency virus infection and/or frank acquired immune deficiency syndrome. The clinical presentation of the oral lesions may be difficult to distinguish from oral squamous cell carcinoma. The histopathological features are usually characteristic, but occasionally the organisms are scanty and not readily identified, which can preclude obtaining the correct diagnosis and ensuring appropriate management. Histoplasmosis is an unusual and rare cause of chronic non‐healing ulceration in the oral cavity. A case of histoplasmosis involving the oral cavity in an immunocompetent patient is reported, which was not recognized, resulting in the inappropriate management of the condition.     

Oral mucosal diseases: erythema multiforme

Erythema multiforme (EM) is a rare acute mucocutaneous condition caused by a hypersensitivity reaction with the appearance of cytotoxic T lymphocytes in the epithelium that induce apoptosis in keratinocytes, which leads to satellite cell necrosis. EM can be triggered by a range of factors, but the best documented association is with preceding infection with herpes simplex virus (HSV). Most other cases are initiated by drugs. EM has been classified into a number of variants, mainly minor and major forms, as it may involve the mouth alone, or present as a skin eruption with or without oral or other lesions of the mucous membrane. EM minor typically affects only one mucosa, and may be associated with symmetrical target skin lesions on the extremities. EM major typically involves two or more mucous membranes with more variable skin involvement. A severe variant of EM major is Stevens-Johnson syndrome, which typically extensively involves the skin. Both EM major and Stevens-Johnson syndrome can involve internal organs and produce systemic symptoms. Treatment of EM is controversial, as there is no reliable evidence. Precipitants should be avoided or treated and, in severe cases, corticosteroids may be needed. Toxic epidermal necrolysis may be similar to Stevens-Johnson syndrome, but many experts regard it as a discrete disease, and therefore it is not discussed here.     

Oral infections in the immunocompromised patient.

The number of immunocompromised patients is increasing because of iatrogenic immunosuppression and HIV infection. Most have T lymphocyte defects and are prone to develop persistent and severe fungal and viral infections. Oral candidosis and peri-oral herpes simplex infections are particularly common. Other oral lesions may be seen: mouth ulceration is common and periodontal health is impaired.     

Oral manifestations of viral infections in immunocompromised patients.

Viral infections are a significant cause of morbidity and mortality in immunosuppressed patients. It is clear that diseases or medical treatments that have cytostatic or cytotoxic effects on lymphocytes and disrupt cytokine production or activity increase the risk of viral infections. While the rate of viral infection varies with the nature and degree of immunosuppression, it is clear that reactivation of latent virus is the most important determinant of the types of viral infections most frequently noted in immunosuppressed patients result from the reactivation of latent virus. Herpesviruses account for the majority of oral viral infections. Herpes simplex virus, varicella-zoster virus, and Epstein-Barr virus infections nearly always result from reactivation of latent virus, while cytomegalovirus infections, besides presenting as reactivated disease, are almost as likely to present as a primary infection in susceptible hosts. Other viral pathogens potentially of concern in immunocompromised patients are enteric viruses (adenoviruses and coxsackieviruses), human papillomaviruses, and possibly the recently identified human herpesvirus type 6. Ninety-eight percent of herpes simplex virus lesions are caused by reactivated disease and tend to be characterized by large, very painful ulcerative lesions throughout the mouth. Varicella-zoster virus is also rarely seen as primary infection, and the herpes zoster lesions involving cranial nerves can cause significant morbidity, including postherpetic neuralgia, corneal scarring, cranial nerve palsies, and deafness. Distinct oral ulcerative lesions caused by Epstein-Barr virus and cytomegalovirus have only recently been described in detail and are usually associated with disseminated disease. Oral human papillomavirus lesions are noted as warts and condylomas. The contribution of enteric viruses and human herpesvirus type 6 to oral disease in immunosuppressed patients is yet to be determined.     

Oral and perioral herpes simplex virus type 1 (HSV-1) infection: review of its management

Herpes simplex virus type 1 (HSV-1) gives rise to a variety of clinical disorders and is a major cause of morbidity and mortality worldwide. HSV-1 infections are common in oral and perioral area. The aim of the present report was to critically examine the published literature to evaluate the advantages and limitations of therapy of HSV-1 infection in both immunocompetent and immunocompromised patients. Systemic antiviral therapy has been widely accepted as effective for primary herpetic gingivostomatitis. Aciclovir (ACV) 5% cream seems to be the accepted standard topical therapy for herpes labialis, being both effective and well tolerated, although penciclovir 1% cream has been proposed as a potentially useful treatment. Systemic ACV may be effective in reducing the duration of symptoms of recurrent HSV-1 infection, but the optimal timing and dose of the treatment are uncertain. Aciclovir and famciclovir may be of benefit in the acute treatment of severe HSV-1 disease in immunocompromised patients. There is also evidence that prophylactic oral ACV may reduce the frequency and severity of recurrent attack of herpetic infection in immunocompromised patients, but the optimal timing and duration of treatment is uncertain and can vary in different situations.     

Concurrent oral cytomegalovirus and herpes simplex virus infection in association with HIV infection: A case report

Recurrent oral herpes simplex virus lesions are common in both immunocompetent and immunocompromised persons. In contrast, cytomegalovirus-associated intraoral lesions are rarely seen, even in the immunocompromised host. We report a case of concurrent oral herpes simplex virus and cytomegalovirus infection, appearing as an ulcerative lesion of the labial mucosa in a patient with acquired immunodeficiency syndrome. Herpes simplex virus type 1 was shown to be present in the lesion by culture tests, histopathologic examination, immunohistochemistry findings and a direct immunofluorescence assay, and cytomegalovirus by histopathologic examination and immunohistochemistry findings. We deduce that the lesion was due to concurrent herpes simplex virus-1 and cytomegalovirus infection. The patient responded well to 2 weeks of treatment with a high dose of acyclovir.     

The controversial natural history of oral herpes simplex virus type 1 infection

The natural history of oral herpes simplex virus type 1 (HSV‐1) infection in the immunocompetent host is complex and rich in controversial phenomena, namely the role of unapparent transmission in primary infection acquisition, the high frequency of asymptomatic primary and recurrent infections, the lack of immunogenicity of HSV‐1 internalized in the soma (cell body) of the sensory neurons of the trigeminal ganglion, the lytic activity of HSV‐1 in the soma of neurons that is inhibited in the sensory neurons of the trigeminal ganglion and often uncontrolled in the other neurons, the role of keratin in promoting the development of recurrence episodes in immunocompetent hosts, the virus–host Nash equilibrium, the paradoxical HSV‐1‐seronegative individuals who shed HSV‐1 through saliva, the limited efficacy of anti‐HSV vaccines, and why the oral route of infection is the least likely to produce severe complications. The natural history of oral HSV‐1 infection is also a history of symbiosis between humans and virus that may switch from mutualism to parasitism and vice versa. This balance is typical of microorganisms that are highly coevolved with humans, and its knowledge is essential to oral healthcare providers to perform adequate diagnosis and provide proper individual‐based HSV‐1 infection therapy.     

Herpes simplex virus infection: part I--Biology, clinical presentation and latency

Oro-facial manifestations of herpes simplex virus (HSV) infections are very common, and include primary herpetic gingivo-stomatitis, recurrent herpes labialis and recurrent intra-oral herpes. Recent research in molecular biology has advanced our knowledge of the HSV pathogenesis and behavior. Understanding the exact mechanism of HSV latency and reactivation enables improvement of drug therapy and prevention strategies of HSV infections. The aim of this review is to update the recent development in the biological and clinical research related to HSV infection, focusing on oral and perioral lesions.