Bacterial Infection
Fungal Infection
        Candidiasis
        Noncandidal fungal infections
Viral Infections
        Herpes virus
        Nonherpes group virus infections

The multiple protective-barrier functions associated with normal oral mucosa directly affect risk for acute infection. Normal oral mucosa functions to reduce levels of oral microorganisms colonizing the mucosa by means of shedding of the surface layer and to limit penetration of many compounds into the epithelium by maintaining a chemical barrier.[1] 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.[2-8] 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 rises.[9] Patients with prolonged neutropenia are at higher risk for development of serious infectious complications.[10,11] Compromised salivary function can elevate risk for 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.[12-15] Dental management prior to initiation of the cytoreductive therapy can substantially reduce the risk of acute infectious flares.[16-19]

Changes in infection profiles in myelosuppressed cancer patients have occurred over the past 3 decades. This evolving epidemiology has been caused by multiple factors, including use of prophylactic and therapeutic antimicrobial regimens, as well as decreased depth and duration of myelosuppression via growth factor therapy.[20] Gram-positive organisms, including viridans streptococci and enterococci species, are currently 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.[12,4,13-15] Extensive ulceration of sulcular epithelium associated with periodontal disease is not directly observable, yet may represent a source for disseminated infection by a wide variety of organisms. Inflammatory signs may be masked due to the underlying myelosuppression. Thus, neutropenic mouthcare 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 complicate the course of the chemotherapy patient.[16] These lesions should be eliminated prior to initiation of chemotherapy. Prechemotherapy endodontic therapy should be completed at least 10 days prior to initiation of chemotherapy. Teeth with poor prognoses should be extracted, utilizing the 10-day window as a guide. Specific management guidelines are delineated in the NIH Consensus Conference statement.[16,17]

Ill-fitting removable prosthetic appliances can traumatize oral mucosa and increase 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 prior to chemotherapy and adjusted as necessary to reduce risk for trauma. Denture cleansing solutions should be changed daily. In general, dentures should not be worn when the patient has ulcerative mucositis and is neutropenic (e.g., <500 ANC/mm³).

Candidiasis is typically caused by opportunistic overgrowth of C. albicans.[21,22] A number of variables contribute to its clinical expression, including myelosuppression, mucosal injury, and salivary compromise.[4] In addition, antibiotics used during prolonged neutropenia and/or concurrent steroid therapy typically alter oral flora, thereby creating a favorable environment for fungal overgrowth. Final diagnosis must be based on the collective relevant features of the history, risk factor analysis, and physical examination.

Protocols utilizing topical oral antifungal agents appear to have variable efficacy in preventing or treating fungal infection in immunocompromised patients.[23,21,24-29] Several studies have demonstrated the inability of nystatin suspension to effectively reduce incidence of either oropharyngeal or systemic infections caused by Candida in immunocompromised patients receiving chemotherapy or radiation; however, the practice continues in many centers. In contrast, clotrimazole troches and amphotericin oral solutions or tablets may have some efficacy in reducing colonization and treating oropharyngeal infections in cancer patients who are immunocompromised. There is increasing evidence that prophylactic systemic azole antifungals can effectively reduce overall oral fungal colonization levels and reduce the risk of oral candidiasis, with fluconazole being the agent of choice.[27]

Patients with superficial candidiasis should be instructed to:

• Clean the oral cavity prior to administering topical antifungal medication; irrigation and mechanical plaque removal may be necessary prior to drug dosing.



• Remove dentures while medication is being applied to the oral tissues.



• Disinfect oral tissues in addition to dental prostheses.

Use a suspension instead of a troche if xerostomia is present (if a troche is preferred, the patient should rinse or drink water prior to dosing).

Persistent or locally invasive fungal infection, especially when risk for systemic dissemination exists, should be treated with appropriate systemic agents. Although topical antifungal prophylaxis and treatment may clear superficial oropharyngeal infections, topical agents are generally not well absorbed and are ineffective against more deeply invasive fungal infections. Systemic agents are thus indicated for treating all except superficial fungal infections in the oral cavity. Therapeutic doses of fluconazole and itraconazole have been reported to produce effective responses in marrow transplant patients.

Systemic candidal infections represent considerable risk to the myelosuppressed patient; treatment efficacy is limited and triazole-resistant organisms may emerge. Amphotericin B is often the drug of choice for treatment of systemic candidiasis.

An increasing number of different fungal organisms are being associated with oral infection in immunocompromised cancer patients in recent years, and includes infection by species of Aspergillus, Mucormycosis, and Rhizopus.[4] The clinical presentation is not pathognomonic; lesions may appear similar to other oral toxicities. Microbiologic documentation is essential. Systemic therapy must be instituted promptly due to high risk for 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 receiving cancer therapy.[30-38] The severity and impact of these lesions, as well as systemic sequelae are directly related to the degree of immunocompromization 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. 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 proven to drastically reduce the incidence of disease. This primarily includes patients receiving high-dose chemotherapy and undergoing hematopoietic stem cell transplantation. Early diagnosis and prompt therapy remain hallmarks of management. As with other infections, risk for systemic dissemination and morbidity/mortality increases with degree and duration of immunocompromise. The infections can be fatal, depending on degree of immunosuppression. Current studies appear to indicate that patients receiving head and neck radiation are not at increased risk of HSV reactivation specifically related to therapy, although occasional instances of simultaneous oral HSV lesions occurring during therapy have been reported.

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 more recently, valacyclovir regimens.[39-41] 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 due to 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 not receiving antiviral prophylaxis, oral lesions typically emerge concurrent with chemotherapy or chemoradiotherapy during the period of most significant immunosuppression (white blood cell nadir). Typically, in hematopoietic stem cell transplant patients this represents the period a few days prior to transplant 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 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 to 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.

This 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. For patients receiving high-dose chemotherapy, orofacial VZV lesions are typically observed several weeks after cessation of chemotherapy. This is in contrast to 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 for reactivation of VZV essentially extends from approximately 3 to 12 months posttransplant, with allogeneic transplant recipients being at highest risk. Acyclovir, valacyclovir, and famciclovir are currently the primary drugs used for treatment.[42]

Oral lesions associated with CMV have been documented in immunocompromised patients, including those who have undergone marrow transplantation.[4,33,34] 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 due to 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 currently the treatment of choice for acute CMV infection. Improved prophylactic measures have reduced the incidence of both primary and recurrent CMV infections.[43,44]

EBV is linked with tumor development.[45] In addition, oral hairy leukoplakia has been attributed to EBV infection in immunocompromised patients, including those with AIDS and renal transplant. The lesion does not appear to be clinically significant in chemotherapy recipients, however. In contrast, hematopoietic stem cell transplant patients who are immunocompromised for a prolonged period may be at risk for development of EBV-related lymphomas of the head and neck region, especially when T-cell–depleted grafts are used for allogeneic transplant. As such, risk for EBV infection typically emerges months after cessation of myeloablative therapy used for transplant conditioning.

EBV has been associated with nasopharyngeal carcinomas.[46] After treatment (surgical and/or radiation therapy) anti-EBV antibody titers are often noted to decrease; subsequent increase in titers can be associated with recurrence.

Infections caused by nonherpes 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, disappearance of the oral mucosal lesions. Laser surgery or cryotherapy are typically utilized to remove oral HPV lesions when medically or cosmetically necessitated; intralesional injections of interferon alfa may prove effective for recurrent lesions.

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