mucous membranes of the lips and oral cavity, periorbital and perioral skin, and skin above the ... Recognition and Management of Herpes Simplex Mucositis in ... of Medicine; H. Lee Moffitt Cancer Center and Research Institute, Tampa, Fla.
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Recognition and Management of Herpes Simplex Mucositis in Neutropenic Patients Kristi L. Fitzmorris, MD, John N. Greene, MD, Ramon L. Sandin, MD, Theresa Field, MD, University of South Florida College of Medicine; H. Lee Moffitt Cancer Center and Research Institute, Tampa, Fla. Infect Med. 2000;17(6)
Herpesvirus infections in neutropenic patients do not usually present as commonly recognized vesicles but rather as ulcers with a white or hemorrhagic base. Lesions may spread to extraoral sites and cause significant morbidity or may allow entry of resident oropharyngeal flora into the bloodstream. Prophylaxis may be useful in bone marrow transplantation and leukemia patients who are seropositive for herpes simplex virus. Treatment with acyclovir is usually effective, but resistant strains can be selected for in profoundly immunosuppressed patients, who may require prolonged antiviral therapy. Herpes simplex virus (HSV) belongs to the family Herpesviridae. The family is composed of largeenveloped, double stranded, DNAcontaining viruses that are noted for their ability to produce clinically apparent disease as well as latent infections. Transmission occurs through close personal contact. Direct contact with both infected lesions and secretions from asymptomatic HSVexcreting persons can result in infection. HSV1 infection is typically acquired in childhood. Primary infection with HSV may manifest itself clinically or the patient may remain asymptomatic. The incubation period is typically 1 to 26 days after acquisition of the virus. HSV1 infects mucosal and extramucosal sites. The mucous membranes of the lips and oral cavity, periorbital and perioral skin, and skin above the waist are most commonly affected. In immunocompetent persons, the primary infection is typically more severe and prolonged than subsequent infections. The lesions usually heal in 7 to 14 days. [1] HSV1 causes necrosis of the infected epithelial cells with subsequent infiltration of inflammatory cells into the connective tissue. This causes the epithelial cells to become edematous and interstitial fluid to become more abundant, which leads to the formation of vesicles. [2] Large, multinucleated cells with molded nuclei, eosinophilic intranuclear inclusions, and a surrounding halo can be found at the base of lesions caused by herpesvirus infection; this aids in microscopic diagnosis. Infected cells lack cytoplasmic inclusions. After the patient recovers from the initial infection, the virus remains latent in sensory ganglia until it is reactivated. This asymptomatic, quiescent state may last for weeks to years. When the patient is exposed to an inciting agent or is immunosuppressed, reactivation of viral replication can occur. This reactivation occurs despite the presence of neutralizing antibodies against the virus. HSV infection is commonly reactivated in bone marrow transplantation patients and in patients with hematologic malignancies, including leukemia and lymphoma. [3,4] Risk factors for reactivation in these patients include neutropenia and disruption of the normal mucosal barriers. Both cellular and antibodymediated immune responses are thought to be important, with the T cells being the primary or firstline defense. It is the deficiency of T cells and Tcell function, accompanied by neutropenia, that contributes to reactivation of infection. The mucosal disruption secondary to chemotherapy, dental prosthesis, nasogastric intubation, and tracheal intubation also contributes to the proliferation of HSV. [5,6] Following bone marrow transplantation, significant oral mucous membrane inflammation begins. This is followed by whitening of the mucosa, hyperemia, ulceration, and formation of white plaques. The peak occurrence of this mucositis (inflammation of the mucous membranes) occurs just before the mean time of HSV reactivation. [4] In several studies, it has been shown that this mucositis often occurs without HSV infection. Therefore, clinical manifestations cannot be relied on exclusively to diagnose HSV infection. [7,8] In immunocompromised patients, endogenous reactivation, rather than exogenous reinfection, most frequently leads to HSV infections. [46] The lesions become clinically apparent approximately 17 days after the onset of neutropenia. [4,5]
HSV infections. [46] The lesions become clinically apparent approximately 17 days after the onset of neutropenia. [4,5] Before the onset of these lesions, patients may develop systemic symptoms, including lymphadenopathy, fever, and malaise, with focal prodromal symptoms of tingling, burning, itching, and pain several hours before the eruption. The lesions begin as vesicles, which rapidly progress and spontaneously rupture. This leads to ulcerations that enlarge, coalesce, and form a crust. [2,5,9] The classic vesicular stage seen in immunocompetent patients may be missed in immunocompromised patients because of this rapid transformation of the lesions. The lesions are commonly localized but can enlarge peripherally, producing extensive necrosis, known as herpes phagedena. [1,9] These large areas of mucosal disruption are the result of inadequate inflammatory and immune responses, which ordinarily would keep the infections localized. Extensive involvement of hard and soft palate, oropharynx, floor of the mouth, labial mucosa, tongue, and extraoral sites, including the vermilion borders of the lips and the philtrum, can be seen[5,8] (Figures 1 and 2). These lesions can extend to contiguous areas and may persist and enlarge for months. Although less common, herpetic whitlow, zosteriform pattern, and widely disseminated disease may predominate. [2,3,9] Superinfection with bacteria and fungi is also seen, which may obscure the diagnosis. [1,2,9] These lesions cause significant morbidity, including increased risk of local and systemic infection, pain and discomfort, and decreased oral nutrition.
Severe hemorrhagic herpes labialis in a patient in whom neutropenia developed following chemotherapy for acute myelogenous leukemia. The herpes progressed rapidly without treatment (A). After 2 weeks of acyclovir therapy and resolution of neutropenia, the hemorrhagic lip lesion had improved significantly (B).
Severe hemorrhagic herpes labialis in a patient in whom neutropenia developed following chemotherapy for acute myelogenous leukemia. The herpes progressed rapidly without treatment (A). After 2 weeks of acyclovir therapy and resolution of neutropenia, the hemorrhagic lip lesion had improved significantly (B).
Hemorrhagic tongue lesions caused by herpes simplex virus in a patient in whom neutropenia developed following chemotherapy for acute myelogenous leukemia (A). Diffuse hemorrhagic mucositis consistent with acyclovirresistant herpes simplex virus developed while the patient was being treated with intravenous acyclovir (B).
Hemorrhagic tongue lesions caused by herpes simplex virus in a patient in whom neutropenia developed following chemotherapy for acute myelogenous leukemia (A). Diffuse hemorrhagic mucositis consistent with acyclovirresistant herpes simplex virus developed while the patient was being treated with intravenous acyclovir (B). The differential diagnosis of mucositis in a neutropenic patient following chemotherapy includes four possibilities: Chemotherapyinduced, varying from high inducers, such as cytosine arabinoside, to low inducers, such as 5 fluorouracil. HSV reactivation. Infection with Candida species (spectrum includes erythematous to pseudomembranous). Anaerobic stomatitis, most often from infection with Capnocytophaga ochraceus; this is difficult to diagnose except in more severe cases, when bacteremia ensues[10] (Figure 3).
Hemorrhagic lesion of the gums in a patient with aplastic anemia caused by infection with Capnocytophaga ochraceus;
such lesions are easily confused with those of herpes simplex. Herpes stomatitis in itself is not usually a lifethreatening infection, but associated infections can cause serious morbidity and death. Candidemia and Streptococcus viridans bacteremia occur more frequently in neutropenic patients with mucositis. [11,12] Candida infection has been associated with dissemination to visceral organs and S viridans infection has been associated with adult respiratory distress syndrome. Both may cause sepsis and death in a substantial number of patients. In addition, spread of herpesvirus infection to the esophagus and lungs can become lifethreatening, especially if an endotracheal tube is present. Therefore, prevention or early recognition with prompt treatment of herpes stomatitis is essential in patients with prolonged neutropenia. Identification of patients at risk for HSV reactivation makes it possible to institute prophylactic therapy. It has been shown that patients seropositive for HSV antibodies have a 70% to 80% chance of reactivation, compared with seronegative patients, who have an insignificant risk. [5,9,13,14] High antiHSV titers have been linked to higher risks of reactivation. [5] Following bone marrow transplantation or intensive chemotherapy for hematologic malignancy, prophylaxis for herpes simplex is indicated in patients who are at risk for reactivation as defined by positive serum HSV titers. Prophylaxis consists of oral acyclovir, 400 mg bid or tid, or oral famciclovir, 125 or 500 mg bid. If oral intolerance develops, intravenous acyclovir, 5 mg/kg every 8 to 12 hours, can be given. For active infection, therapy with acyclovir (400 mg tid) has been shown to decrease the duration of viral shedding, reduce symptom intensity, and expedite healing time. [2,4,15] Acyclovir is highly selective against viruses encoding for thymidine kinase. The phosphorylation of the medication occurs primarily in HSVinfected cells, leading to viral inactivation. There is a low toxicity associated with acyclovir because of the specificity of its action. Therapy should be continued until immunosuppression is reversed. [5,16] Famciclovir can also be used at a dosage of 500 mg bid in patients who are immunosuppressed. If oral intolerance develops, intravenous acyclovir, 5 mg/kg tid, is indicated. Valacyclovir can also be used for prophylaxis and therapy (500 mg bid or 1 g bid or tid, respectively). Acyclovirresistant viruses are becoming an increasing problem in highly immunosuppressed patients, especially in those who have received allogeneic bone marrow transplantation or those receiving frequent courses of prophylaxis with antiherpesvirus regimens. In one study, 5% to 14% of immunocompromised patients proved to have infections that were resistant to acyclovir. These patients have either a deficiency or an alteration of thymidine kinase. [17] Fortunately, the virus may remain susceptible to antivirals acting on DNA polymerase, such as foscarnet, 60 to 90 mg/kg every 12 hours. [1,4,18] Resistance should be considered in highrisk patients with prolonged viral shedding who are receiving appropriate therapy. [14] The lack of immediate response to acyclovir does not always imply resistance. Acyclovir is a virustatic drug; therefore, patients with profound immunodeficiency may need a prolonged course of treatment before improvement becomes evident. [5] In addition, apparent resistance to therapy in patients receiving oral acyclovir has sometimes been shown to be caused by lack of compliance with therapy. [4] In conclusion, herpesvirus infections in neutropenic patients do not usually present as commonly recognized vesicles but rather as ulcers with a white or hemorrhagic base. Progressive enlargement of the area with spread to proximal sites down the GI and respiratory tracts may occur in the persistently neutropenic patient if treatment is not begun. Oral acyclovir, famciclovir, or valacyclovir, or intravenous acyclovir when indicated, is appropriate for therapy. Drug resistance is suspected if the lesion fails to respond after 7 days of appropriate therapy or if the lesion recurs after initial improvement while the patient is receiving appropriate therapy. Viral culture should be obtained and foscarnet instituted. Herpes prophylaxis in highrisk groups and early recognition and therapeutic intervention should reduce the incidence of severe associated bacterial and fungal infections and the morbidity of active herpesvirus infection. Appropriate therapy is intravenous acyclovir, 5 to 10 mg/kg every 8 hours, or equivalent dosages adjusted for renal insufficiency. References
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