The multiple protective-barrier functions associated with normal oral mucosa directly affect risk of acute infection. Normal oral mucosa reduces levels of oral microorganisms colonizing the mucosa by shedding the surface layer; it also limits penetration of many compounds into the epithelium by maintaining a chemical barrier. Normal salivary gland function promotes mucosal health.
Oral mucositis can be complicated by infection in the immunocompromised patient. Specific organisms may play a role in upregulating proinflammatory cytokines via bacterial metabolic products such as liposaccharides. Also, oral organisms can disseminate systemically in the setting of ulcerative oral mucositis and profound, prolonged neutropenia.[2-5]
Both indigenous oral flora and hospital-acquired pathogens have been associated with bacteremias and systemic infection. As the absolute neutrophil count falls below 1,000/mm3, incidence and severity of infection rise. Patients with prolonged neutropenia are at higher risk of developing serious infectious complications.[7,8] Compromised salivary function can elevate risk of infection of oral origin.
Other oral sites, including the dentition, periapices, and periodontium, can also become acutely infected during myelosuppression secondary to high-dose chemotherapy.[9-12] A systematic review of the MEDLINE/PubMed and EMBASE databases for articles published between January 1, 1990, and December 31, 2008, reported (from three studies) that the weighted prevalence of dental infection/abscess during chemotherapy was 5.8% (standard of error, 0.009; 95% confidence interval [CI], 1.8–9.7). Dental management before cytoreductive therapy is initiated can substantially reduce the risk of these infectious complications.[14-16]
Changes in infection profiles in myelosuppressed cancer patients have occurred over the past three decades. This evolving epidemiology has been caused by multiple factors, including the use of prophylactic and therapeutic antimicrobial regimens and decreased depth and duration of myelosuppression via growth factor therapy. Gram-positive organisms, including viridans streptococci and Enterococci species, are associated with systemic infection of oral origin. In addition, gram-negative pathogens, including Pseudomonas aeruginosa, Neisseria species, and Escherichia coli, remain of concern.
Myeloablated cancer patients with chronic periodontal disease may develop acute periodontal infections, with associated systemic sequelae.[3,9-12] Extensive ulceration of sulcular epithelium associated with periodontal disease is not directly observable yet may represent a source of disseminated infection by a wide variety of organisms. Inflammatory signs may be masked by the underlying myelosuppression. Thus, neutropenic mouth care protocols that reduce microbial colonization of the dentition and periodontium are important during myelosuppression. Topical therapy may include the following:
- Oral rinses with 0.12% chlorhexidine digluconate.
- Irrigation with effervescent (peroxide) agents, which may affect anaerobic bacteria colonizing the periodontal pocket.
- Gentle mechanical plaque removal, including dental brushing and flossing.
Pulpal/periapical infections of dental origin can cause complications for the chemotherapy patient. Such lesions should be eliminated before chemotherapy begins. Prechemotherapy endodontic therapy should be completed at least 10 days before chemotherapy begins. Teeth with poor prognoses should be extracted, using the 10-day window as a guide. Specific management guidelines are delineated in the NIH Consensus Conference statement.[14,15]
Ill-fitting, removable prosthetic appliances can traumatize oral mucosa and increase the risk of microbial invasion into deeper tissues. Denture-soaking cups can readily become colonized with a variety of pathogens, including P. aeruginosa, E. coli, Enterobacter species, Staphylococcus aureus, Klebsiella species, and Candida albicans. Dentures should be evaluated before chemotherapy begins and adjusted as necessary to reduce risk of trauma. Denture-cleansing solutions should be changed daily. In general, dentures should not be worn when the patient has ulcerative mucositis and is neutropenic (i.e., absolute neutrophil count <500 cells/mm3).
Candidiasis is typically caused by opportunistic overgrowth of C. albicans, a normal inhabitant of the oral cavity in a large proportion of individuals. Several variables contribute to its clinical expression, including drug- or disease-induced immunosuppression, mucosal injury, and salivary compromise. In addition, use of antibiotics may alter the oral flora, thereby creating a favorable environment for fungal overgrowth.
A systematic review indicated that the weighted mean prevalence of clinical oral fungal infection during chemotherapy is 38%. The most common forms of intraoral candidiasis reported in oncology patients are pseudomembranous and erythematous candidiasis.[20,21] Pseudomembranous candidiasis can usually be diagnosed on the basis of its characteristic clinical appearance and may be accompanied by burning pain and taste changes. The appearance of erythematous candidiasis is relatively nonspecific, and laboratory testing may be needed to confirm the diagnosis. It may be accompanied by a burning sensation of the affected tissues.
Topical oral antifungal agents such as nystatin rinse and clotrimazole troches are often used but appear to have variable efficacy in preventing or treating fungal infection in neutropenic patients.[22,23] Patients who wear removable dental prostheses (e.g., partial or full denture) should remove them before the oral antifungal agents are used. Dentures can also be treated by soaking them overnight in the antifungal solution.
Although topical agents may be helpful for superficial oral candidiasis, systemic agents should be used for persistent fungal infections and in patients with significant immunosuppression. Systemic fluconazole is highly effective for prophylaxis and treatment of oral fungal infections in the oncology population.
Noncandidal fungal infections
An increasing number of different fungal organisms are being associated with oral infection in immunocompromised cancer patients, including infection by species of Aspergillus, Mucormycosis, and Rhizopus.[3,23] The clinical presentation is not pathognomonic; lesions may appear similar to lesions caused by other oral toxicities. Microbiologic documentation is essential. Systemic therapy must be instituted promptly because of the high risk of morbidity and mortality.
Herpes group viral infections, including those caused by oral lesions, can cause a variety of diseases that range from mild to serious conditions in patients undergoing treatment for cancer. The severity and impact of these lesions and systemic sequelae are directly related to the degree of immunocompromisation of the patient. Comorbid oral conditions such as mucositis or graft-versus-host disease can dramatically increase the severity of oral lesions and significantly increase the difficulty of diagnosis.
In most instances, herpes simplex virus (HSV), varicella-zoster virus (VZV), and Epstein-Barr virus (EBV) infections result from reactivation of latent virus, while cytomegalovirus (CMV) infections can result from either reactivation of a latent virus, or via a newly acquired virus. The viral infections can cause oral mucosal lesions. The prevalence of HSV infection was found to be higher when oral ulcers existed than when no oral ulcers were present.
A systematic review was conducted by the Mucositis Study Group (MSG) of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology. One of the aims of this review was to evaluate studies conducted since 1989 that considered the prevalence of oral viral infections. The reported prevalence of oral HSV infection was 49.8% (95% CI, 31.3–68.2%) among neutropenic cancer patients. The prevalence was much lower in head and neck cancer (HNC) patients who were treated with radiation therapy (0%); however, it rose to 43.2% (95% CI, 0–100%) in irradiated HNC patients who were treated with radiation therapy combined with chemotherapy. This finding is not surprising because neutropenic patients—mainly patients with hematological malignancies—develop deeper immunosuppression during cancer treatment than do other groups of cancer patients. However, the addition of chemotherapy to the conventional radiation therapy increased risks for HNC patients.
With the recognition of the increased risk of HSV and VZV reactivation in seropositive patients who are expected to become profoundly immunosuppressed during cancer therapy, prophylaxis with antiviral medications has drastically reduced the incidence of disease, primarily in patients receiving high-dose chemotherapy and undergoing hematopoietic stem cell transplant (HSCT). The MSG systematic review identified a series of randomized controlled trials testing various antiviral prophylactic protocols. It concluded that there was a significant benefit to using acyclovir to prevent HSV oral infection (at 800 mg/d).[Level of evidence: I] In addition, the systematic review pointed out that HSV reactivation was reported in a similar prevalence whether acyclovir or valacyclovir was prescribed  and that the prevention of HSV reactivation was achieved in various dosing protocols of valacyclovir (500 or 1,000 mg/d).
The Centers for Disease Control and Prevention (CDC), the Infectious Diseases Society of America (IDSA), and the American Society for Blood and Marrow Transplantation (ASBMT) have published guidelines for the prevention of opportunistic infections in HSCT recipients, which have become a benchmark in this field.[28,29] This significant body of literature presents a global perspective on the prevention of viral infections. CDC, IDSA, and ASBMT concluded that acyclovir prophylaxis is recommended for all HSV seropositive allograft recipients. Valacyclovir instead of acyclovir has been ranked moderately as an effective prevention for HSV in HSCT; foscarnet was mentioned as a drug to avoid for routine HSV prophylaxis because of substantial renal toxicity.
These guidelines extend beyond the MSG systematic review, which failed to provide sufficient evidence (e.g., regarding CMV, VZV, and EBV infections) because the evidence available is not specific for infections with oral involvement. The guidelines of these three U.S. societies are in line with the recommendations of the German Society of Hematology  and the European Group for Blood and Marrow Transplantation.
Early diagnosis and prompt therapy remain hallmarks of management. Unfortunately, the available literature  and the CDC and ASBMT guidelines [28,29] do not refer to treatment recommendations once a viral infection is diagnosed. As with other infections, risk of systemic dissemination and morbidity/mortality increases with degree and duration of immunocompromisation. The infections can be fatal, depending on degree of immunosuppression.
Herpes simplex virus
Oral herpetic lesions can range from routine herpes labialis to severe stomatitis causing large, painful ulcerations throughout the mouth. The severity of lesions dramatically increases with increasing degrees of immunosuppression. The incidence of recurrent oral HSV lesions in myelosuppressed cancer patients has been considerably reduced with the use of prophylactic acyclovir and valacyclovir regimens.[32-34] Additionally, the severity and duration of actual HSV lesions have been reduced by antiviral therapies.
Breakthrough infections are uncommon but can occur. While true resistance to antivirals occurs, clinical infection in the face of antiviral therapy is more likely caused by insufficient dosing or compromised gastrointestinal absorption of oral acyclovir. The introduction of valacyclovir appears to have reduced the incidence of breakthrough oral HSV infections. Topical therapy alone is generally not efficacious in the immunocompromised patient.
In patients who are not receiving antiviral prophylaxis, oral lesions typically emerge concurrent with chemotherapy or chemoradiation therapy during the period of most significant immunosuppression (white blood cell nadir). Typically, in HSCT patients, this represents the period a few days pretransplant through day 35 posttransplant. The risk of HSV reactivation remains higher than normal until immune reconstitution occurs. Similar patterns of risk are noted in patients who are receiving high-dose (immunosuppressive) chemotherapy.
Recurrent oral HSV infections occurring simultaneously with cancer therapy–induced oral mucositis can result in the development of extensive, confluent mucosal ulcerations clinically similar to primary herpetic stomatitis. As such, HSV stomatitis can be confused with cancer therapy–induced ulcerative mucositis. Viral cultures from lesions in HSV seropositive patients are essential for accurate diagnoses. Assays that produce more rapid results, including direct immunofluorescence, shell vial testing, and specific immunoassay for HSV antigen and/or biopsy, may also be useful.
Unlike in myelosuppressed cancer patients, incidence of HSV reactivation in patients undergoing head and neck radiation is very low. Therefore, HSV prophylaxis in patients scheduled to receive head and neck radiation is not recommended.
VZV infection classically distributes via dermatomes, although the clinical manifestations can be altered in immunocompromised patients, and multiple dermatomes or more widespread distribution of lesions can be seen. In patients who are receiving high-dose chemotherapy, orofacial VZV lesions are typically observed several weeks after cessation of chemotherapy—unlike HSV, which often occurs within 2 to 3 weeks after chemotherapy is discontinued. For reasons that are not entirely clear, the period of increased risk of VZV reactivation essentially extends from approximately 3 to 12 months posttransplant, with allogeneic transplant recipients being at highest risk. Acyclovir, valacyclovir, and famciclovir are the primary drugs used for treatment.
Oral lesions associated with CMV have been documented in immunocompromised patients, including those who have undergone marrow transplantation.
Appearance is not pathognomonic and is characterized by multiple mild to moderate ulcerations with irregular margins. The lesions initially present during early periods of marrow regeneration (e.g., 3 weeks after chemotherapy is discontinued) and are characterized by nonspecific pseudomembranous fibrin exudate-covered ulcerations with a granulomatous-appearing base. Surface swab cultures may yield false-negative results, perhaps because of viral propensity for infecting endothelial cells and fibroblasts, with resulting low levels of free virus.
Shell vial cultures can enhance identification of CMV, but CMV-specific immunohistochemical staining of biopsy specimens remains the gold standard. Ganciclovir is the treatment of choice for acute CMV infection. Improved prophylactic measures have reduced the incidence of both primary and recurrent CMV infections.[Level of evidence: I]
EBV is linked to tumor development. In addition, oral hairy leukoplakia has been attributed to EBV infection in immunocompromised patients, as seen in HIV-infected patients and solid organ transplant patients. The lesion does not appear to be clinically significant in chemotherapy recipients, however. In contrast, HSCT patients who are immunocompromised for a prolonged period may be at risk of developing EBV-related lymphomas of the head and neck region, especially when T-cell–depleted grafts are used for allogeneic transplant. As such, risk of EBV infection typically emerges months after cessation of myeloablative therapy used for transplant conditioning.
EBV has been associated with nasopharyngeal carcinomas. After treatment (surgery and/or radiation therapy), anti-EBV antibody titers are often noted to decrease; subsequent increases in titers can be associated with recurrence.
Non–herpes group virus infections
Infections caused by non-herpes viruses are more common in immunocompromised patients, with the risk of infection apparently increasing with the depth and duration of immunosuppression. Oral lesions caused by adenovirus and oral human papilloma virus (HPV) have been described. Often, patients with increased cutaneous HPV lesions will demonstrate oral lesions. These lesions can present as hyperkeratotic verrucoid lesions or as flat acuminata-like lesions.
Restoration of immune function will often result in a digression and, possibly, the disappearance of the oral mucosal lesions. Laser surgery or cryotherapy are typically used to remove oral HPV lesions when medically or cosmetically required; intralesional injections of interferon-alpha may prove effective for recurrent lesions. Infection with Coxsackie viruses can occur but is generally viewed as uncommon. Although adenovirus infections are often implicated as a potential cause of oral lesions, their true incidence is not known.
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