| Add RSS Feed

October 16, 2007

Introduction

Human organ transplantation, a topic of science fiction in past years, is now a reality. Development of various immunosuppressive agents such as cyclosporine (cyclosporine A (or CyA) and tacrolimus (FK 506) has minimized the significance of obtaining a perfect tissue match between donor and recipient. These advances will further increase the clinical application of human-to-human organ transplantation in coming years.¹ Significant clinical aspects of immunosuppressive agents used in organ transplantation are listed in the table entitled Immunosuppressive drugs: summary of indications, mechanisms, metabolism in precautions, and influence on dental treatment, which can be accessed and downloaded from the Clinical Decision-Making Tools section at www.thesystemiclink.com.

To ensure optimal clinical outcomes of organ transplantation, it is critical for medical, dental, and allied healthcare professionals to be familiar with prevention, identification, and/or treatment of the oral complications associated with pre- and post-organ transplant therapies. Wynn and colleagues² have described the following oral/facial complications associated with immunosuppressive drugs:

• Gingival hypertrophy/enlargement
• Mouth ulcers
• Dysphasia
• Salivary gland enlargement
• Gingival bleeding
• Gingivitis
• Xerostomia
• Glossitis
• Abnormal taste
• Mouth odor
• Fungal (Candida) infections
• Herpes simplex
• Esophagitis
• Oral moniliasis
• Stomatitis
• Nonmelonoma skin carcinoma
• Lymphadenopathy
• Petechia
• Increased gingival hemorrhage
• Anemia

In addition to drug-induced gingival enlargement, other prevalent yet often unrecognized threats to successful organ transplantation arise from the risk of developing other oral/facial complications, including certain types of de novo malignancies, as well as viral, bacterial, or fungal infections associated with periodontal disease. Therefore, collaborative care is critical to the success of organ transplantation, as reflected in concordant dental care recommendations for patients before and after organ transplantation.

Increased risk of gingival enlargement associated with immunosuppressive drugs

Cyclosporine is a potent immunosuppressant used in organ transplant recipients, with side effects including nephrotoxicity, neurotoxicity, hepatoxicity, hypertrichosis, hypertension, and gingival overgrowth.^2,3 Gingival lesions were first reported in 1978 with results of the first clinical trials on cyclosporine.⁴ Gingival enlargement occurs in approximately 8-70% of the patients taking the medication, with an overall incidence of approximately 25-30%.^5-9 However, up to 97% of pediatric heart and lung transplant recipients demonstrate some degree of cyclosporine A-induced overgrowth.¹⁰ Statistical reporting can be confounded by other drugs taken concomitantly with cyclosporine.^5,6,11 For example, calcium channel blockers are often given for cyclosporine-induced hypertension, and this combination is associated with gingival overgrowth.² Cyclosporine is also used with adjunctive prednisolone or azathioprine for post-transplant therapy; however, these agents have an inverse relationship with occurrence of gingival enlargement.¹² Overall, risk factors for cyclosporine A-induced gingival enlargement include dose, concomitant use with calcium channel blockers, and genetic predisposition (Table 1). Clinical features of immunosuppressive drug-induced gingival enlargement are described in Table 2, and shown in Figures 1-3. Further information from numerous authors on the risk factors, clinical manifestations, and pathogenesis of drug-induced gingival enlargement is summarized in the 2004 report of the American Academy of Periodontology on Drug Associated Gingival Enlargement.¹³

Tacrolimus is used as a “rescue therapy” in organ transplant cases with ongoing rejection, and for patients who have developed a ctclosporine A-induced nephrotoxicity.^1-3 It has also become an effective alternative to cyclosporine therapy for primary immunosuppression in pediatric renal transplant cases.^1-3 The most common side effects of tacrolimus include anemia, renal toxicity, hyperkalemia, chronic diarrhea and allergies.² The gingival hyperplasia, hypertension, and hirsuitism observed with cyclosporine are not seen with tacrolimus.^29-31 This may be related to:

• Secreted protein acidic and rich in cystein (SPARC), a glycoprotein that mediates cell-matrix interactions. SPARC mRNA levels tended to increase 72 hours after cyclosporine A treatment while they are undetectable in FK 506-treated fibroblasts.³²
• Increased matrix metalloproteinase-1 (MMP-1 gene) and metalloproteinase-2mRNA (MMP-2 gene), which may be important for regulating collagen type I (COL-1) homeostasis in the gingival connective tissue compartment of FK 506-immunosuppressed subjects.³²
• A role of ECM stabilization that may be associated with FK 506, and does not overdo the gingival overgrowth.³³

Patients may be converted to tacrolimus with minimal risk of allograft dysfunction or rejection.^29,34 After switching from cyclosporine to tacrolimus, cyclosporine-related gingival hyperplasia and hypertrichosis resolve almost completely, mean total cholesterol is reduced, and mean systolic and mean diastolic blood pressures are reduced.^31,34

Increased risk of developing certain types of “de novo” malignancies

Transplant recipients are also at an increased risk of developing the following de novo malignancies seen in the dental setting:

• Epithelial dysplasia - (3 to 7 fold increased risk)³⁵
• Squamous oral carcinoma, especially of the lip in CsA treated patients^36-38
• Basal cell carcinoma³⁹
• Lymphoma (lymphoproliferation disease), non-Hodg-kin’s lymphoma - (2 to 3 fold increased risk) ⁴⁰
• Kaposi’s sarcoma^41,42
• Cervical carcinoma⁴³
• Human papilloma^35,42

The incidence of these de novo malignancies increases progressively with length of time after transplantation, ranging from 10% after 10 years, to 40% after 20 years post-transplant.³⁶ Human papilloma virus DNA has been detected in the tumors, suggesting that immunosuppression may have a permissive effect on viral proliferation.³⁵ Prior to the availability of appropriate antiviral drugs (e.g., acyclovir, gancyclovir and valacyclovir), approximately 50% of renal allograft recipients (who were seropositive for herpes simplex) experienced recurrent, severe, and prolonged HSV infections.^44-46 Long-term post-allograft immunosuppression may predispose patients to human herpesvirus 8 (HHV-8) and associated Kaposi’s sarcoma.⁴² However, anti-herpetic regimens have significantly reduced the frequency of HSV infections.⁴⁷

Increased risk of infection associated with periodontal disease in immunocompromised patients

Underlying periodontal disease can affect the successful outcome of an organ transplant via direct and indirect pathways. Untreated dental infections or oral mucosal lesions can jeopardize renal function in the newly transplanted kidney.⁴⁸ It has been hypothesized that periodontal disease should be viewed on the basis of the model of virus-bacteria-host immune response interaction which may account for the gingival inflammation episodes reported by several authors.^28,49 Acute periodontal infections in myelosuppressed cancer patients are associated with high concentrations of subgingival plaque - predominantly Staphhylococcus epidermidis, Candidia albicans, Staphylococcus aureus, and Pseudomonas aeruginosa - and in some patients a concomitant bacteremia.⁵⁰ Pathogens that are normally associated with infections in myelosuppressed cancer patients, as well as indigenous oral flora, are associated with acute periodontal infections during granulocytopenia.⁵⁰ These findings highlight the mouth as a source for acute infections in immunosuppressed patients.

Role of bacterial plaque biofilms in cyclosporine-induced gingival enlargement

Plaque accumulation has been strongly associated with gingival overgrowth, both in the animal model of cyclosporine A-induced gingival enlargement⁵¹ and in a large group of cyclosporine A-treated allograft patients using a multivariate regression analysis model.⁵² Oral hygiene status including bacterial plaque, calculus, and bleeding must be assessed before administration of the drugs. Patients with evidence of an inflammatory gingival overgrowth before initiating cyclosporine A treatment are more likely to develop severe gingival enlargement.⁵³ However, a large study of cyclosporine A-treated patients failed to fully explain the distribution of gingival overgrowth based solely on the level of plaque and gingivitis.⁵⁴ Some studies have suggested that while plaque biofilm can probably modify the characteristics, it is not essential for the development of gingival overgrowth.^55-57 The relationship between gingival inflammation and the development of gingival overgrowth is still unclear, although a positive relationship has been suggested.¹⁴ There is no agreement in the literature regarding the effects of home care and professional plaque control on gingival enlargement.

Role of inflammatory cytokines in periodontal disease and solid organ transplant deterioration

Periodontal pathogens can potentially cause a bacteremia that might eventually lead to the rejection of the transplanted organs, and a great deal of research is focused on the role of inflammatory cytokines in the periodontal-systemic connection. Interleukin (IL)1β is a pro-inflammatory cytokine that is elevated in inflamed gingival tissues.¹³ Histological examination of cyclosporineA-induced gingival lesions has revealed a dramatic elevation in IL-6 expression by cells within the gingival connective tissue.^58,59 Inflammation plays a role in organ transplant rejection, and levels of serum IL-6 can identify individuals who are at greater risk for transplant rejection.⁶⁰ Although cyclosporine A therapy does not directly increase IL-1β and IL-6 levels in the gingival fluid, inflammation associated with cyclosporine A-induced gingival lesions might be more directly responsible for cyclosporine A-induced tissue overgrowth.⁵⁸ Ioannidou and colleagues⁶⁰ reported that transplant recipients with chronic periodontitis had significantly higher serum IL-6 levels than those without chronic periodontitis, that there was a positive correlation between periodontal IL-6 gene expression levels and serum IL-6 protein levels, and that periodontal tissue destruction and local IL-6 synthesis are associated with elevated IL-6 levels in transplant recipients. This may have serious implications in solid organ transplant deterioration and chronic rejection.

Role of herpesvirus infections in systemic and periodontal disease

Herpesvirus infections affect cytokine-chemokine networks,^49,61,62 as cytokines and chemokines play important roles in the first line of defense against human herpesvirus infections, and also contribute significantly to the regulation of acquired immune responses.

Human Cytomegalovirus (HCMV) infection induces a proinflammatory cytokine profile, with production of interleukin (IL)-1β, IL-6, IL-12, tumor necrosis factor alpha (TNF-α), interferon (IFN)-α/β, IFN-γ,⁶² and prostaglandin E₂ (PGE₂).⁶³ HCMV is the most common viral pathogen encountered in all solid organ recipient populations,^61,64 and the most common infectious reason for transplant rejection, including bone marrow and stem cell grafts.⁶⁴ Infection can occur by transfer of virus with the allograft or by reactivation of latent virus remotely acquired by the recipient.⁴⁹ Seronegative recipients who acquire organs from seropositive donors are at greatest risk of developing infection, and these primary infections tend to be most severe. The use of antilymphocyte antibody therapy for immunosuppression after organ transplantation also enhances the likelihood and the severity of infection in susceptible recipients.⁶⁵ HCMV infection typically emerges 1-3 months after transplantation, although onset may be delayed in patients receiving antiviral prophylaxis, which may suggest a reactivation of a latent virus.⁶⁵ HCMV infection appears to enhance the overall level of host immunosuppression, possibly accounting for frequent emergence of other opportunistic infections and presenting strong evidence for the role of herpesvirus in the pathogenesis of human periodontal disease.⁶⁶ Despite antiviral therapy, renal transplant patients affected by periodontitis are at risk of viral replication within the periodontal tissues, as the periodontal pockets may serve as a reservoir for HCMV replication.⁶⁷

HCMV infection seems to be a significant risk factor for the development of bacterial septic infection in liver transplant recipients,^61,68,69 and for causing colonization of the oropharynx by gram-negative bacilli in renal transplant recipients.⁷⁰ A herpesvirus periodontal infection has the potential to increase the level and pathogenicity of specific periodontopathic pathogens. In a study of 140 adults with gingivitis or periodontitis, periodontal Epstein Barr Virus (EBV-1) and HCMV were related to the elevated occurrence of the pathogens Porphyromonas gingivalis, Porphyromonas forsythus, Prevotella intermedia, Prevotella nigrescens, and Treponema denticola.⁶⁶ In patients who are immunocompromised, activation of the herpesvirus may therefore play a major role as activator of the periodontal disease process.⁴⁹

Opportunistic infections in immunosuppressed patients

Post-transplant recipients are immunocompromised and therefore at increased risk for opportunistic infections and complications that lead to significant morbidity and mortality. Some infections involve more than one pathogen, e.g., pneumonia may have viral, bacterial, or fungal etiology.² All immunosuppressed patients are at risk from bacteremia from oral microorganisms. Daily bacteremia from chewing or tooth brushing is most likely the cause of systemic infections, rather than dental treatment⁷¹, in light of American Heart Association (AHA) recommended premedication regimens for all dental procedures.⁷¹ In spite of the recent changes issued by the AHA in the Prevention of Infective Endocarditis (IE) Guidelines in April 2007, numerous comorbid factors - such as older age, diabetes mellitus, immunosuppressive conditions or therapy, and dialysis - may complicate IE, which further increases morbibity and mortality rates in organ transplant recipients.⁷² Furthermore, in light of drug side effects and compromised renal clearance, controversy remains in the national and international medical communities regarding antibiotic prophylaxis.⁴² In a survey of U.S. organ transplants, among the 294 survey responses (38% response rate), 85% recommended antibiotic prophylaxis prior to dental care, and 96% recommended the 1997 AHA endocarditis prevention regimen.⁷³ It is the opinion of the authors of this article that since solid organ transplant recipients are in a drug-induced immunosuppressed state, they should continue to receive antibiotic prophylaxis; as with any medication; however, the risk of an adverse event associated with the antibiotic must not exceed the benefit. Since most cases of IE are not attributable to an invasive procedure, but rather to randomly occurring bacteremias from routine daily activities, this is reason enough to ensure that the patient has healthy plaque-free teeth and inflammation-free gingiva, to reduce the risk of infections associated with odontogenic bacteria.⁷⁴

Increased risk for Candida and Aspergillus infections

In organ transplant recipients treated with cyclosporine A, C. albicans is the most frequent species identified in the saliva; C. dubliniensis, C. parapsilosis, C. krusei, and C. tropicalis are also found.³⁶ In patients treated with tacrolimus, C. albicans and C. dublieniensis are found.³⁶ The same Candida hyphae have been seen invading the gingival epithelium.²⁶ The presence of Candida in an immunosuppressed patient should come as no surprise since yeasts are opportunistic organisms. Aspergillus species is an opportunistic and endemic fungi that has also been reported to cause serious infections in organ transplant recipients. It is by far the most frequent and lethal fungal pathogen occurring in 5% of liver, lung, and heart transplant patients, and less frequently in kidney transplant patients.⁶⁵

Collaborative approaches to care of organ transplant recipients

Most patients are severely immunocompromised from post-transplant medications; therefore, dental professionals must first consult with the transplant recipient’s attending physician before beginning any dental treatment. Conversely, the patient’s physician should have the potential transplant candidate obtain a complete dental and periodontal evaluation before the patient can be fully considered for an organ transplant. Historically, collaborative care for organ transplant patients has at best taken a multidisciplinary approach, but with the growing number of transplant cases, a more comprehensive transdisciplinary approach is more appropriate. The transdisciplinary team members are more committed to the patient’s total care by sharing responsibility, and each member is accountable for how the plan is implemented. This approach requires extreme dedication by each team member in order to provide optimal care; information regarding the patient’s health status and progress is assessed, observed, recorded, and shared with all specialties involved in the patient’s care.⁷⁵

Concordant recommendations for dental care in pre-organ transplant recipients

Many patients with end stage renal disease (ESRD) are in poor health for a long time as they await potential organ transplantation. In fact, the majority of patients with renal disease will show oral symptoms such as changes in the teeth, bone and periodontium. Oral manifestations of patients with chronic renal failure receiving hemodialysis include malodor ‘bad breath,’ and a metallic taste which is due to the high urea content in saliva and its subsequent breakdown to ammonia.⁷⁶ The patients appear to be predisposed to xerostomia.⁷⁷ Patients with dry mouth are often prone to retrograde parotitis; these complications are believed to result from a combination of direct gland involvement, chemical inflammation, dehydration and mouth breathing.⁴⁸ Children with renal disease can have premature tooth loss and dental developmental abnormalities such as delayed eruption, enamel hypoplasia and narrowing of the pulp chamber.^42,77 Bone resorption can lead to pathologic tooth mobility and drifting.^42,78 A wide range of bone anomalies can arise in chronic renal disease due to defects of calcium metabolism with resultant secondary hyperparathyroidism, affecting up to 92% of the patients receiving hemodialysis.⁷⁹ The bony features that may be seen include decreased trabeculation, bone demineralization, decreased thickness of cortical bone, “ground glass appearance of bone”, radiolucent fibrocystic lesions and radiolucent giant cell lesions.^42,78 Abnormal healing after extractions may occur.⁴² (For information on dental management of patients with renal disease, please see “Oral Health and Chronic Kidney Disease: Building a Bridge Between the Dental and Renal Communities” in this issue of Grand Rounds.)

Furthermore, because these patients are severely immunocompromised, many of them are suffering from bacterial and fungal infections (which are often under-treated due to the severity of the existing kidney failure and the extensive medications they are taking for ESRD).⁸⁰ Periodontal disease, dental caries and poor plaque control are often ignored, and these issues can potentially be life threatening in the renal transplant patient. In the 1998 study⁸⁰ of 4 renal dialysis centers in Virginia, the renal dialysis sample studied had 100% prevalence of periodontal disease, which is greater than the 85% seen in the general population. The authors of that study suggested that a stringent continued care program be established to prevent oral disease from progressing undetected. Bleeding tendencies in these patients were attributed to a combination of factors, including anticoagulants used with hemodialysis therapy and vascular access maintenance. The reduction in the platelet counts and platelet adhesion and increased capillary fragility can all lead to an increase in the loss of blood during dental procedures.⁷⁶

The following general recommendations for dental therapy in prior to solid organ transplantation are based on the work of various expert sources and the clinical experience of the authors of this article.

⇒ Obtain a medical consult from the patient’s nephrologists to discuss recent coagulation values, and medications, including steroids and administration of antibiotic prophylaxis.^76,78

⇒ Consider hematologic conditions that most commonly affect the patient with uremia and renal failure: anemia and excessive bleeding. Obtain white blood cell count and platelet count, and bleeding time should be obtained before proceeding with surgical dental procedures including extractions. Hematocrit, hemoglobin and differential blood tests should be performed to evaluate for anemia. Note that bleeding can be a significant problem in patients on dialysis because warfarin or heparin therapy is used to prevent clotting in the shunt.^76-78

⇒ Conduct comprehensive periodontal and restorative examinations and develop comprehensive treatment plans before the patient receives the transplant.

⇒ Conduct a complete series of radiographs for on all dentate patients. A panoramic radiograph is sufficient for edentulous patients. Caries, periodontal disease, cysts, tumors, impacted teeth, periapical lesions and any pathological condition needs to be addressed.⁷⁸

⇒ Give special attention to the head, neck and oral cancer examination due to the predilection for skin cancers and lymphomas.^41,43 Any suspicious lesions and/or localized or diffuse swellings should be examined further by the attending physician.

⇒ Eliminate local bacterial plaque factors through meticulous home care instructions and plaque control techniques. Consider a sonic electric toothbrush,⁸¹ and oral irrigator if needed. The patient must attain acceptable dental health. Parents of pediatric patients should also receive oral hygiene instructions to better assist and/or supervise their child.

⇒ Perform mechanical debridement.

⇒ Use chlorhexidine 0.12% mouth rinse which may be beneficial^28,82 as an anti-fungal and antimicrobial. It should be used as a pre-operative rinse for all dental procedures.

⇒ Consider systemic antibiotics during scaling and root planing. Use caution with certain antibiotics due to nephrotoxicity.⁷⁸

⇒ Conduct supportive periodontal maintenance while the patient is on dialysis at an interval determined by the patients needs; every 3-4 months may prove helpful.

⇒ Conduct dental procedures the day after dialysis.^78,83 If a new shunt is being placed, then it is best to wait two weeks before initiating treatment. NO dental treatment should be performed if there is any infection or clotting at the site of the shunt. Complications with the shunt can lead to infective endocarditis.

⇒ Try to save teeth via endodontic therapy (preferred over extraction).

⇒ Analyze saliva and gingival crevicular fluid for active HCMV infection.⁶⁷

⇒ Consider hematologic conditions that most commonly affect the patient with uremia and renal failure: anemia and excessive bleeding. Obtain white blood cell count and platelet count, and bleeding time should be obtained before proceeding with surgical dental procedures including extractions. Hematocrit, hemoglobin and differential blood tests should be performed to evaluate for anemia. Note that bleeding can be a significant problem in patients on dialysis because warfarin or heparin therapy is used to prevent clotting in the shunt.^76,78

⇒ Perform minimally invasive extractions at least 8 hours after dialysis. Meticulous surgical technique should be followed. Use hemostatic agents and suturing to ensure hemostasis. If necessary, the dialysis regimen can be modified and Vitamin K therapy can be considered.⁴²

⇒ Prescribe fluoridated toothpaste and/or fabricate custom fluoride trays for at-home fluoride application if decay is a problem.

⇒ Educate patient regarding the connection of periodontal disease and their role in the success or failure of renal dialysis and renal transplantation.

⇒ Follow current AHA recommendations⁷³ for premedication for all dental procedures, due to the increased risk of infection for the uremic patient on dialysis.^42,72,78,83

⇒ Use postoperative antibiotics. Penicillin, erythromycin, amoxicillin, and clindamycin are preferred; these antibiotics may be used in usual doses for a short course of therapy.⁷⁸

⇒ Manage pain. Acetaminophen, propoxyphene hydrochloride, pentazocine and codeine can be used in moderate amounts, and the dosages should be adjusted. Avoid aspirin and meperidine hydrochloride.^76,78,83

Concordant recommendations for dental care in post-organ transplant recipients

The following general recommendations for dental therapy in solid organ transplant recipients are based on the work of various expert sources and the clinical experience of the authors of this article.

⇒ After consultation with the medical team members, consider switching from cyclosporin to tacrolimus for significant resolution or complete regression of the gingival enlargement.²⁶

⇒ Advise the patient to follow an oral hygiene program prior to transplant surgery.⁸⁴ Oral hygiene instructions should include:

√ Extra soft brush for sensitive teeth
√ Chlorhexidine 0.12% mouth rinse BID^78,85,86
√ Mild toothpastes with low abrasive qualities and no added whitening or tartar control products which can be irritating in a dry mouth
√ Non-alcohol containing mouthwashes

⇒ Conduct quadrant scaling and root planing⁵⁶ to possibly help resolve the inflammation, which may eliminate the need for surgery;⁸⁷ at least 12 months of oral hygiene, subgingival scaling, and periodontal maintenance therapy is most effective in resolving the inflammation.⁸⁸

⇒ Perform microbial culture and antibiotic sensitivity test to best determine that the etiology is bacterial and not fungal, since Candida hyphae have been found in the gingival lesions as previously pointed out.

⇒ Freqeuntly monitor saliva and gingival crevicular fluid for active HCMV infection; this may reduce the risk of transplant complications due to HCMV infection.⁶⁷

⇒ Use caution when prescribing an antibiotic due to potential nephrotoxicity.^2,78

⇒ For slight to moderate gingival enlargement, use systemic antibiotics. If treated early, condition responds well to azithromycin 250-500 mg/per day for 3-5 days.^89-91 Azithromycin may lead to amelioration or complete regression of the gingival overgrowth and the duration of the effects may be 3 months to 2 years.⁹⁰ Another study contradicted the findings stating that azithromycin and/or metronidazole do not really cause regression of the overgrowth but act on the concomitant bacterial infection and gingival inflammation.⁹²

⇒ For bleeding on probing or cyclosporine A-induced gingival overgrowth, use azithromycin-containing toothpaste (85 mg of azithromycin per gram of toothpaste).⁹³

⇒ If Candida is identified, use topical antifungal medications. Regimens include clotrimazole troche 10 mg (1 troche slowly dissolved in mouth five times a day for 14 consecutive days), and nystatin oral suspension 5 ml (1 teaspoon - hold in mouth for 2 minutes and swallow) QID.²

⇒ For angular cheilitis, use nystatin ointment (applied to the lesion) QID until healing occurs.²

⇒ For xerostomia, use over-the-counter (OTC) moisturizing toothpaste, alcohol-free, anti-bacterial mouthwash, sugar-free gum to stimulate salivary flow, mouth moisturizing gel or mouth spray, synthetic saliva-aqueous solution, or prescriptions for 1.1% neutral sodium fluoride toothpaste, 0.63% stannous fluoride rinse concentrate, or 0.4% stannous fluoride gel to minimize the potential for root caries in the adult patient.^2,76

⇒ Children with chronic renal failure (CRF) have significantly lower isolation frequency of Streptococcus mutans,⁹⁴ but it significantly increases 3 months post transplant.⁹⁴ Caries may become more significant in children post-transplant. Use fluoride rinses or at-home fluoride application trays if necessary.

⇒ For gingival enlargement, scalpel or laser excision is necessary if the excess tissue is unsightly and/or interferes with mastication, speech or oral care.²⁶ The classical surgical approach has been gingivectomy, however an alternative periodontal flap approach has also been suggested,¹¹ to limit the large denuded connective tissue wound seen in the gingivectomy. This alternative approach minimizes post operative pain and bleeding, permits healing by primary intention,⁹⁵ and possibly prevents or limits the overzealous healing or faster cell proliferation of the injured connective tissue especially when plaque control is difficult after surgeries and the tissue regrowth may easily recur. Recurrence rate of severe cyclosporine A-induced gingival enlargement after surgery is about 40% within 18 months.⁹⁵ (Figure 3.) The recurrence rate was found to be higher in younger patients with greater existing gingival inflammation and who are poorly compliant to the recommended maintenance visit schedule.⁹⁵ Regular re-motivation and professional care at frequent recalls after periodontal surgery is important.⁹⁶

⇒ To minimize the risk of adrenal crisis in individuals who have taken large doses of corticosteroids (10 mg prednisolone daily during the preceding 3 months) and are undergoing surgical procedures (including extractions of more than one tooth), appropriate corticosteroid cover should be administered.^42,78

⇒ Biopsy of the excised tissues is recommended due to the risk of epithelial dysplasias, lymphoproliferative diseases and carcinomas reported in organ transplant recipients.⁹⁷

Conclusion

Although advances in immunosuppressive regimens, surgical techniques, organ preservation, and overall management of transplant recipients have improved graft and patient survival, infectious complications remain a major obstacle. Bacterial, fungal, and viral infections are implicated after transplant surgery as causes for organ rejection. Recognition of infection as a serious complication following solid organ transplantation supports the need for pre-transplant screening, early diagnosis of active infection, and modalities for prevention and treatment of various infections. Proper prophylactic and treatment strategies are imperative when dealing with chronic immunosuppression, nosocomial and host pathogens, emerging drug resistance, multiple drug interactions and medication toxicities.

The interrelationship between periodontal inflammation and systemic diseases has been established, and inflammation plays a critical role in organ transplant rejection. Periodontal disease can have serious detrimental effects on the successful long-term outcome of patients receiving organ transplants. Long term transplant survival in these patients may depend on eliminating the negative effects of periodontal disease, through careful consideration of the use of localized and systemic antibiotics, antimicrobial rinses, frequent recalls, and good daily plaque control.

Collaborative care integrates various disciplines and team members responsible for the patient’s health, and the dentist and dental hygienist can play an integral role on the transplant team in establishing a clinical protocol that assists the organ transplant recipient in maintaining optimal oral health. The transdisciplinary approach is ideal, but may be difficult to achieve in the private practice setting where the lines of communication are more difficult to maintain. In the hospital/medical center setting, each team member would more likely be able to commit to meeting regularly to share information and to teach and learn across disciplines.

Disclosures

Jon B. Suzuki, DDS, PhD, MBA serves on the scientific advisory boards of Biohorizons and Philips Oral HealthCare.

References

1. Kaufman DB, Shapiro R, Lucey MR, et al. Immunosuppression: practice and trends. Am J Transplant. 2004;4(Suppl 9):38-53.
2. Wynn RL, Meiller TF, Crossley, HL. Drug Information Handbook for Dentistry. 12th edition. Hudson, OH:Lexi-Comp, Inc. 2006:168-169 (azathioprine); 405-411 (cyclosporine); 1075-1077 (mycophenolate); 1397-1399 (sirolimus); 1437-1444 (tacrolimus).
3. Seymour R, Heasman P. Drugs, Diseases and the Periodontium. Oxford, Oxford University Press. 1992.
4. Calne RY, White DJ, Thiru S, et al. Cyclosporin A in patients receiving renal allografts from cadaver donor. Lancet. 1978;2(8104-8105):1323-1327.
5. Seymour RA, Heasman PA. Drugs and the periodontium. J Clin Periodont.1988;15(1):1-16.
6. Lundergan WP. Drug-induced gingival enlargements. Dilantin hyperplasia and beyond. J Calif Dent Assoc. 1989;17(6):48-52.
7. Palestine AG, Nussenblatt RB, Chan CC. Side effects of systemic cyclosporin in patients not undergoing transplantation. Am J Med. 1984;77(4):652-656.
8. Boltchi FE, Rees TD, Iacopino AM. Cyclosporine A-induced gingival overgrowth: a comprehensive review. Quintessence Int. 1999;30(11):775-783.
9. Daley TD, Wysocki GP. Cyclosporin therapy - its significance to the periodontist. J Periodontol. 1984;55(12):708-712.
10. Kilpatrick, NM, Weintraub RG, Lucas JO, et al. Gingival overgrowth in pediatric heart-lung transplant recipients. J Heart Lung Transplant. 1997;16:1231-1237.

11. Seymour RA. Calcium Channel blocker and gingival overgrowth [review]. Br Dent J. 1991;170(10):376-379.
12. Wilson RF, Morel A, Smith D, et al. Contribution of individual drugs to gingival overgrowth in adult and juvenile renal transplant patients treated with multiple therapies. J Clin Periodontol. 1998; 25(6):457-464.
13. Dongari-Bagtzoglou A. Research, Science and Therapy Committee, American Academy of Periodontology. Drug-associated gingival enlargement [review]. J Periodontol. 2004;75(10):1424-1431.
14. Seymour RA, Ellis JS, Thomason JM. Risk factors for drug-induced gingival overgrowth [review]. J Clin Periodontol. 2000;27(4):217-223.
15. Radwan-Oczko M, Boratynska M, Klinger M, et al. Risk factors of gingival overgrowth in kidney transplant recipients treated with cyclosporin A. Ann Transplant. 2003;8(4):57-62.
16. Thomason JM, Ellis JS, Kelly PJ, et al. Nifedipine pharmacological variables as risk factors for gingival overgrowth in organ-transplant patients. Clin Oral Invest. 1997;1(1):35-39.
17. James JA, Marley JJ, Jamal S, et al. The calcium channel blocker used with cyclosporin has an effect on gingival overgrowth. J Clin Periodontol. 2000;27(2):109-115.
18. Morisaki I, Fukui N, Fujimori Y, et al. Effects of combined oral treatments with cyclosporine A and nifedipine or diltiazem on drug-induced gingival overgrowth in rats. J Periodontol. 2000;71(3):438-443.
19. Thomason J, Seymour R, Ellis J, et al. Determinants of gingival overgrowth severity in organ transplant recipients: an examination of the role of the HLA phenotype. J Clin Periodontol. 1996;23(7):628-634.
20. Cebeci I, Kantarci A, Firatli E, et al. Evaluation of the frequency of HLA determinants in patients with gingival overgrowth induced by cyclosporin A. J Clin Periodontol. 1996; 23(8):737-742.

21. Brunicardi CF, Andersen DK, Billiar TR, et al. Schwartz’s Principles of Surgery, Eighth Edition. The McGraw-Hill Companies, Inc; 2005:295-331.
22. Meraw SJ, Sheridan PJ. Medically induced gingival hyperplasia. Mayo Clin Proc. 1998;73(12):1196-1199.
23. Wysocki GP, Gretzinger HA, Laupacis A, et al. Fibrotic enlargement of the gingiva: A side effect of cyclosporin. Oral Surg Oral Med Oral Pathol. 1983;55(3):274-278.
24. Marshall RI, Bartold PM. A clinical review of drug-induced gingival overgrowth [review]. Aust Dent J. 1999;44(4):219-232.
25. Hallmon WW, Rossman JA. The role of drugs in the pathogenesis of gingival overgrowth. A collective review of current concepts [review]. Periodontol 2000. 1999;21:176-196.
26. Khocht A, Schneider LC. Periodontal management of gingival overgrowth in the heart transplant patients: a case report. J Periodontol. 1997;68(11):1140-1146.
27. Thomason J, Kelly P, Seymour R. The distribution of gingival overgrowth in organ transplant patients. J Clin Periodontol. 1996;23(4):367-371.
28. Farge P, Ranchin B, Cochat P. Four year follow-up of oral health surveillance in renal transplant children. Pediatr Nephrol. 2006;21(6):851-855.
29. James JA, Boomer S, Maxwell AP, et al. Reduction in gingival overgrowth associated with conversion from cyclosporin A to tacrolimus [review]. J Clin Periodontol. 2000;27(2):144-148.
30. Asanti-Korang A, Boyle GJ, Webber SA, et al. Experience of FK506 immune suppression in pediatric heart transplantation: a study of long-term adverse effects. J Heart Lung Transplant. 1996;15(4):415-422.

31. Thorp M, De Mattos A, Bennett W, et al. The effect of conversion from cyclosporin to tacrolimus on gingival hyperplasia, hirsuitism and cholesterol. Transplantation. 2000;69(6):1218-1220.
32. Gagliano N, Moscheni C, Dellavia C, et al. Immunosuppression and gingival overgrowth: gene and protein expression profiles of collagen turnover in FK506-treated human gingival fibroblasts. J Clin Periodontol. 2005;32(2):167-173.
33. Gagliano N, Moscheni C, Torri C, et al. Differential effect of cyclosporin A and FK 506 on SPARC mRNA expression by human gingival fibroblasts. Biomed Pharmacother. 2005;59(5):249-252.
34. Margreiter R, Pohanka E, Sparacino V, et al.; the European Switch to Tacrolimus Study Group. Open prospective multicenter study of conversion to tacrolimus therapy in renal transplant patients experiencing ciclosporin-related side-effects. Transpl Int. 2005;18(7):816-823.
35. Euvrard S, Kanitakis J, Claudy A. Skin cancers after organ transplantation [review]. N Engl J Med. 2003;348(17):1681-1691.
36. Spolidorio LC, Spolidorio DMP, Massucato EMS, et al. Oral health in renal transplant recipients administered cyclosporine A or tacrolimus. Oral Dis. 2006;12(3):309-314.
37. Regev E, Zeltser R, Lustmann J. Lip carcinoma in renal allograft recipient with long-term immunosuppressive therapy. Oral Surg Oral Med Oral Pathol. 1992;73(4):412-414.
38. Thomas DW, Seddon SV, Shepherd JP. Systemic immunosuppression and oral malignancy: a report of a case and review of the literature. Br J Oral Maxillofac Surg. 1993; 31(6):391-393.
39. Hyckel P, Schleier P, Meerbach A, et al. The therapy of virus-associated epithelial tumors of the face and the lips in organ transplant recipients. Med Microbiol Immunol. 2003;192(3):171-176.
40. Cockfield SM. Identifying the patient at risk for post-transplant lymphoproliferative disorder. Transpl Infect Dis. 2001;3(2):70-78.

41. Qunibi WY, Akhtar M, Ginn E, et al. Kaposi’s sarcoma in cyclosporin-induced gingival hyperplasia. Am J Kidney Dis. 1988;11(4):349-352.
42. Proctor R, Kumar N, Stein A, et al. Oral and dental aspects of chronic renal failure. J Dent Res. 2005;84(3):199-208.
43. Varga E, Tyldesley WR. Carcinoma arising in cyclosporin-induced gingival hyperplasia. Br Dent J. 1991;171(1):26-27.
44. Korsager B, Spencer ES, Mordhorst CH, et al. Herpesvirus hominis infections in renal transplant recipients. Scand J Infect Dis. 1975;7(1):11-19.
45. Naraqi S, Jackson CG, Jonasson O, et al. Prospective study of prevalence, incidence and source of herpesvirus in patients with renal allografts. J Infect Dis. 1977;136(4):531-540.
46. Armstrong JA, Evans AS, Rao N, et al. Viral infections in renal transplant recipients. Infect Immun. 1976;14(4):970-975.
47. Kletzmayr J, Kreuzwieser E, Watkins-Riedel T, et al. Long-term oral gancyclovir prophylaxis for prevention of cytomegalovirus infection and disease in cytomegalovirus high-risk transplant recipients. Transplantation.2000;70(8):1174-1180.
48. Eigner TL, Jastak JT, Bennett WM. Achieving oral health in patients with renal failure and renal transplants. J Am Dent Assoc. 1986;113(4):612-616.
49. Slots J. Herpesviral-bacterial synergy in the pathogenesis of human periodontitis. Curr Opin Infect Dis. 2007;20(3):278-283.
50. Peterson DE, Minah GE, Overholser CD et al. Microbiology of acute periodontal infections in myelosuppressed cancer patients. J Clin Oncol. 1987;5(9):1461-1486.

51. Hassell TM, Roebuck S, Page RC, et al. Quantitative histopathologic assessment of developing phenytoin-induced gingival overgrowth in the cat. J Clin Periodontol. 1982; 9(5):365-372.
52. Fu E, Nieh S, Wikesjo UM. The effect of plaque retention on cyclosporin-induced gingival overgrowth in rats. J Periodontol. 1997;68(1):92-98.
53. Varga E, Lennon MA, Mair LH. Pre-transplant gingival hyperplasia predicts severe cyclosporin-induced gingival overgrowth in organ transplant patients. J Clin Periodontol. 1998; 25:225-230.
54. Thomas DW, Newcombe RG, Osborne GR. Risk factors in the development of cyclosporine-induced gingival overgrowth. Transplantation. 2000;69(4):522-526.
55. Seymour RA, Smith DG. The effect of a plaque control programme on the incidence and severity of cyclosporin-induced gingival changes. J Clin Periodontol. 1991;18(2):107-110.
56. Somacarrera ML, Lucas M, Scully C, et al. Effectiveness of periodontal treatments on cyclosporine-induced gingival overgrowth in transplanted patients. Br Dent J. 1997;183(3):89-94.
57. Ellis JS, Seymour RA, Taylor JJ, et al. Prevalence of gingival overgrowth in transplant patients immunosuppressed with tacrolimus. J Clin Periodontol. 2004;31(2):126-131.
58. Atilla G, Kutukculer N. Crevicular fluid interleukin-1beta, tumor necrosis factor-alpha, and interleukin-6 levels in renal transplant patients receiving cyclosporine A. J Periodontol. 1998;69(7):784-790.
59. Williamson MS, Miller EK, Plemons J, et al. Cyclosporin-A upregulates interleukin-6 gene expression in human gingiva: possible mechanisms for gingival overgrowth. J Periodont. 1994;65(10):895-903.
60. Ioannidou E, Kao D, Chang N, et al. Elevated serum interleukin-6 (IL-6) in solid organ transplant recipients is positively associated with tissue destruction and IL-6 gene expression in the periodontium. J Periodontol. 2006;77(11):1871-1878.

61. Slots, J. Herpesviruses in periodontal diseases [review]. Periodontology 2000. 2005;38:33-62.
62. Mogensen TH, Paludan SR. Molecular pathways in virus-induced cytokine production. Microbiol Mol Biol Rev. 2001:65(1):131-150.
63. Mocarski ES. Virus self-improvement through inflammation: no pain, no gain. Proc Natl Acad Sci, USA. 2002;99(6):3362-3364.
64. Clark DA, Emery VC, Griffiths PD. Cytomegalovirus, human herpesvirus-6 and human herpesvirus-7 in hematological patients [review]. Semin Hematol. 2003;40(2):154-162.
65. Kotloff RM, Ahya VN, Crawford SW. Pulmonary complications of solid organ and hematopoietic stem cell transplantation [review]. Am J Resp Crit Care Med. 2004;170(1):22-48.
66. Contreras A, Umeda M, Chen C et al. Relationship between herpesviruses and adult periodontitis and periodontopathic bacteria. J Periodontol. 1999;70(5):478-484.
67. Nowzari H, Jorgensen MG, Aswad S, et al. Human cytomegalovirus-associated periodontitis in renal transplant patients. Transplant Proc. 2003;35(8):2949-2952.
68. Mutimer D, Mirza D, Shaw J, et al. Enhanced (cytomegalovirus) viral replication associated with septic bacterial complications in liver transplant recipients. Transplantation. 1997;63(10):1411-1415.
69. Paya CV, Weisner RH, Hermans PE, et al. Risk factors for cytomegalovirus and severe bacterial infection following liver transplantation: a prospective multivariate time-dependent analysis. J Hepatol. 1993;18(2):185-195.[Erratum: J Hepatol 1993;19(2):325.]
70. Mackowiak PA, Goggans M, Torres W, et al. Relationship between cytomegalovirus and colonization of the oropharynx by gram-negative bacilli following renal transplantation. Epidemiol Infect. 1991;107(2):411-420.

71. Roberts GJ. Dentists are innocent! “Everyday” bacteremia is the real culprit: a review and assessment of the evidence that dental surgical procedures are a principal cause of bacterial endocarditis in children [review]. Pediatr Cardiol. 1999;20(5):317-325.
72. Wilson W, Taubert KA, Gewitz M, et al. Prevention of infective endocarditis: guidelines from the American Heart Association: a guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group. J Am Dent Assoc. 2007;138(6):739-745, 747-760.
73. Guggenheimer J, Mayher D, Eghtesad B. A survey of dental care protocols among U.S. organ transplant centers. Clin Transplant. 2005:19;15-18.
74. Lucas VS, Roberts GJ. Oral-dental health in children with chronic renal failure and after transplantation: a clinical review [review]. Pediatr Nephrol. 2005;20(10):1388-1394.
75. Garland CG, McGonigal JJ, Frank A, et al. The transdisciplinary model of service delivery. Lightfoot, VA: Child Development Resource.1989.
76. De Rossi SS, Glick M. Dental considerations for the patient with renal disease receiving hemodialysis [review]. J Am Dent Assoc. 1996;127(2):211-219.
77. Vesterinen M, Ruokonen H, Leivo T, et al. Oral health and dental treatment of patients with renal disease. Quint Int. 2007;38(3):211-221.
78. Svirsky JA, Nunley J, Dent D, et al. Dental and medical considerations of patients with renal disease [review]. J Calif Dent Assoc. 1998;26(10):762-770.
79. Massry SG, Ritz E. The pathogenesis of secondary hyperparathyroidism of renal failure: is there a controversy? Arch Intern Med. 1978;138(Spec No):853-856.
80. Naugle K, Darby ML, Bauman DB, et al. Oral health status of individuals in renal dialysis. Ann Periodontol. 1998;3(1):197-205.

81. Smith JM, Wong CS, Salamonik EB, et al. Sonic tooth brushing reduces gingival overgrowth in renal transplant recipients. Pediatr Nephrol. 2006;21(11):1753-1759.
82. Lee SC, Fung CP, Lin CC, et al. Porphyromonas gingivalis bacteremia and subhepatic abscess after renal transplantation: a case report. J Microbiol Immunol Infect. 1999;32(3):213-216.
83. Vasanthan A, Dallal N. Periodontal treatment considerations for cell transplant and organ transplant patients. Periodontology 2000. 2007;44(1):82-102.
84. Somacarrera ML, Hernández, G, Acero J, et al. Factors related to the incidence and severity of cyclosporin-induced gingival overgrowth in transplant patients. A longitudinal study. J Periodontol. 1994;65(7):671-675.
85. Jones CG. Chlorhexidine: is it still the gold standard? Periodontol 2000. 1997;15:55-62.
86. Pilatti GL, Sampaio JE. The influence of chlorhexidine on the severity of cyclosporin A-induced gingival overgrowth. J Periodontol. 1997;68(9):900-904. [Erratum in: J Periodontol. 1998;69(1):102.]
87. Kantarci A, Cebeci I, Tuncer O, et al. Clinical effects of periodontal therapy on the severity of cyclosporine A-induced gingival hyperplasia. J Periodont. 1999;70(6):587-593.
88. Aimetti M, Romano F, Debernardi C. Effectiveness of periodontal therapy on the severity of cyclosporine A-induced gingival overgrowth. J Clin Periodontol. 2005;32(8):846-850.
89. Gomez E, Sanchez-Nunez M, Sanchez JE, et al. Treatment of cyclosporin-induced gingival hyperplasia with azithromycin. Nephrol Dial Transplant. 1997;12(12):2694-2697.
90. Strachan D, Burton I, Pearson GJ. Is oral azithromycin effective for the treatment of cyclosporin-induced gingival hyperplasia in cardiac transplant recipients? J Clin Pharm Ther. 2003;28(4):329-338.

91. Nowicki M, Kohot F, Wiecek A. Partial regression of advanced cyclosporin-induced gingival hyperplasia after treatment with azithromycin. A case report. Ann Transplant. 1998;3(3):25-27.
92. Mesa FL, Osuma A, Aneiros J, et al. Antibiotic treatment of incipient drug-induced gingival overgrowth in adult renal transplant patients. J Periodontol Res. 2003;38(2):141-146.
93. Argani H, Pourabbas R, Hassanzadeh D, et al. Treatment of cyclosporine-induced gingival overgrowth with azithromycin- containing toothpaste. Exp Clin Transplant. 2006;4(1):420-424.
94. Al Nowaiser A, Lucas VS, Wilson M, et al. Oral health and caries related microflora in children during the first three months following renal transplantation. Int J Paediatr Dent. 2004;14(2):108-126.
95. Pilloni A, Camargo PM, Carere M, et al. Surgical treatment of cyclosporin A- and nifedipine-induced gingival enlargement: gingivectomy versus periodontal flap. J Periodontol. 1998;69(7):791-797.
96. Ilgenli T, Atilla G, Baylas H. Effectiveness of periodontal therapy in patients with drug-induced gingival overgrowth. Long term results. J Periodontol. 1999;70(9):967-972.
97. Rolland SL, Seymour RA, Wilkins BS, et al. Post-transplant lymphoproliferative disorders presenting as gingival overgrowth in patients immunosuppressed with ciclosporin. A report of two cases. J Clin Periodontol. 2004;31(7):581-585.

    Susan M. Chialastri, DMD Associate Professor, Department of Periodontology and Oral Implantology, Temple University, Maurice H. Kornberg School of Dentistry, Philadelphia, PA

    Jon B. Suzuki, DDS, PhD, MBA Professor of Microbiology-Immunology, School of Medicine; Professor of Periodontology and Oral Implantology, School of Dentistry; Associate Dean for Graduate Education, Research, and International Affairs; Director, Graduate Periodontology and Oral Implantology, Temple University, Philadelphia, PA

| Add RSS Feed