Transplantation Medicine.pdf

ORAL DIAGNOSIS AND DENTAL RADIOLOGY-II Transplantation Medicine Assoc. Prof. Büşra YILMAZ School of Dental Medicine Department of Oral and Maxillofacial Radiology [email protected] Organ Transplantation Organ transplantation can effectively restore vital organ function in patients sufferin...

ORAL DIAGNOSIS AND DENTAL RADIOLOGY-II Transplantation Medicine Assoc. Prof. Büşra YILMAZ School of Dental Medicine Department of Oral and Maxillofacial Radiology [email protected] Organ Transplantation Organ transplantation can effectively restore vital organ function in patients suffering from a variety of medical conditions In some situations organ transplantation is the only available option and essential for survival, and in other situations it offers the potential for improved disease control and better quality of life Kidney, heart, liver, pancreas, lung, small bowel, bone marrow, and composite tissues (skin, muscle, tendon, nerves, bone, blood vessels) may be considered for transplantation Organ Transplantation Essential principles of organ transplantation involve  Immunology underlying for proper donor and recipient matching  Need for immunosuppressive therapy for prevention and management of graft rejection Organ Transplantation Bone marrow, or hematopoietic cell transplantation (HCT) is unique in that there is no sophisticated surgical procedure, but rather a cellular infusion of hematopoietic stem cells Rather than risk long-term chronic graft rejection, the major immune-mediated complication is graft-versus-host disease (GVHD), in which the engrafted donor immune system attacks the recipient host tissues in an autoimmune-like manner Organ Transplantation Solid organ transplantation is limited primarily by the availability of organ donors and limitations in organ procurement from cadavers In some cases organs are obtained from living donors, primarily with renal and hematopoietic cell transplantation, but also with newer approaches to partial pancreas and liver transplantation Organ Transplantation Organ transplant recipients require comprehensive dental screening and clearance prior to transplantation to reduce infection risk  Long-term immunosuppression  The dentist must understand basic principles of risk assessment and dental treatment planning prior to organ transplantation Immunosuppressive Medications Even in matched solid organ and hematopoietic cell transplants, nonspecific immunosuppressive agents are necessary to prevent acute and chronic graft rejection While effective at preventing and managing rejection, immunosuppressive therapies increases the recipient’s susceptibility to infection and malignancy Pathophysiology and Complications Complications; 1. graft rejection, 2. problems related to chronic immunosuppressive therapy, 3. problems specific to the transplanted organ Graft Rejection A potentially very serious complication of organ transplantation that can occur despite donor-recipient matching and the administration of immunosuppressive medications  Hyperacute rejection of solid organs occurs within 48 hours of surgical anastomosis  Acute rejection occurs within the first 90 days after transplantation  Chronic rejection of solid organs, despite treatment with immunosuppressive medications, is generally irreversible Immunosuppression and Infection Risk Immunosuppressive medications non-specifically block T- and B-cell activity and innate immunity effector cells and pathways, significantly increasing the risk for infection  Donor and recipient screening for major infections prior to transplant is essential to reduce the risk of infectious complications  Transplant recipients also receive extensive education and guidance on other preventive strategies including hygiene, environmental exposures, and food safety handling Immunosuppression and Infection Risk Solid organ transplant recipients require lifelong immunosuppression Patients with chronic rejection or chronic GVHD require more intense immunosuppression Immunosuppression and Infection Risk Patients in the early post-transplant period are at risk for nosocomial infections, opportunistic infections, and donor-derived infections  Invasive fungal infections tend to occur within the first three months of transplantation Patients 1 to 6 months post-transplant face a high risk of opportunistic infections and reactivation of latent infections Infections more than 6 months post-transplant tend to be typical community-acquired, but with more severe manifestations Other Side Effects of Immunosuppression Medications Immunosuppressive medications are associated with various side effects that can have significant medical implications Calcineurin inhibitors (CNI) therapy (cyclosporine and tacrolimus) is associated with development of chronic kidney disease and renal insufficiency that can progress to end stage renal disease Other effects include tremors, magnesium wasting, hypertension, hyperkalemia, hyperuricemia, and hyperglycemia Calcineurin inhibitors (CNI, cyclosporin and tacrolimus) are an important part of treatment to suppress the immune system to prevent rejection of transplanted kidneys Other Side Effects of Immunosuppression Medications Mycophenolate is associated with myelosuppression and gastrointestinal side effects Azathioprine has a similar mechanism of action as mycophenolate but is used less frequently due its less favorable side effect profile Prednisone therapy side effects increase with dose and duration and include hyperglycemia, hypertension, hyperlipidemia, and osteoporosis Mechanistic Target of Rapamycin (mTOR) inhibitors (sirolimus and everolimus) are associated with cytopenia and hyperlipidemia Cancer Risk There is an increased risk for post-transplant lymphoproliferative disease (PTLD) and nonmelanoma skin cancers Post-transplant lymphoproliferative disorders (PTLD) are one of the most important malignancies after solid organ transplantation (SOT) and hematopoietic stem-cell transplant (HSCT), and it develops as a result of uncontrolled B cell proliferation due to blunted immunological surveillance. B cells may get infected by Epstein-Barr virus (EBV) (key pathognomonic driver of PTLD evolution) HCT patients are at increased risk for melanoma, liver, oral cavity, brain, thyroid and bone cancers Organ-Specific Complications Kidney Transplantation There’s a particular risk for BK virus nephropathy BK polyomavirus (BKPyV) is a small DNA virus that establishes lifelong infection in the renal tubular and uroepithelial cells of most of the world's population. For the majority, infection is quiescent and benign. However, in immunocompromised patients, BKPyV can reactivate, and in some, lead to BKPyV-associated nephropathy (BKPyVAN). If graft failure occurs, hemodialysis can be initiated Organ-Specific Complications Heart Transplantation Cardiovascular disease can arise from the donor heart due to preexisting pathology, de novo related to traditional/existing risk factors, or from allograft vasculopathy Recipients receive lifelong statin therapy regardless of lipid levels Organ-Specific Complications Liver Transplantation Both HCV infection and alcohol abuse have high likelihood of recurrence and require routine screening and active treatment if detected Organ-Specific Complications Hematopoietic Cell Transplantation GVHD is potentially life-threatening where engrafted donor lymphocytes mount a multifaceted alloimmune-mediated attack against the recipient/host tissue Solid organ transplantation very rarely involves GVHD, though in facial transplantation, graft rejection of skin and oral mucosa presents clinically and histopathologically identical to GVHD Clinical Presentation Transplant recipients generally have normal physiologic function and performance status, similar to the general population, if the graft “takes” with no chronic rejection or GVHD Depending on the degree and extent of organ function compromise, the clinical presentation of solid organs may resemble that of the pretransplant disease status Signs and symptoms of GVHD vary, but include skin rash, diarrhea, fibrosis, oral lichenoid inflammation and sensitivity, and eye discomfort Dental Management Due to a period of profound immunosuppression following transplantation, it is standard of care for all organ transplant candidates to undergo pre-transplant dental screening and clearance in order to reduce risk of infectious complications Patients should perform basic oral care to reduce the risk of inflammation, and local or systemic infection Patients with a history of gingivitis or periodontitis may benefit from daily chlorhexidine gluconate rinses, often included in the oral care regimen at HCT centers Removable prostheses should be cleaned manually and soaked overnight in a disinfecting solution Dental Management There are no universally agreed upon indications for antibiotic prophylaxis prior to dental treatment in transplant patients American Heart Association (AHA) guidelines recommend antibiotic prophylaxis in cardiac transplant recipients who develop valvulopathy AHA prophylaxis regimens have also been recommended for patients on immunosuppressive therapy for dental treatment infection risk American Academy of Pediatric Dentistry (AAPD) infection risk prophylaxis guidelines recommend prophylactic antibiotics per AHA guidelines Risk Assessment The important aspect of assessing patient risk is knowing medical history and status:  indication for transplantation,  organ function status,  current medications,  pertinent laboratory results, and  transplantation schedule and timeline Patients may be at risk for bleeding due to antithrombotic therapy, anticoagulant therapy, advanced liver disease, or thrombocytopenia, and therefore, require careful evaluation of medication history and partial thromboplastin time (PTT) and prothrombin (PT)/International Normalized Ratio (INR) Pre-transplant Dental Screening and Clearance The objective of pre-transplant dental screening and clearance is to reduce the risk of infection in the immediate post-transplant period of immunosuppression Dental screening is considered standard of care at all transplant centers to reduce overall infection risk Pre-transplant Dental Screening and Clearance The pre-transplant dental screening should include; Dental history Full-mouth series of dental radiographs Vitality testing Periodontal evaluation Assessment of third molars Treatment of all dental caries Management of pulpal infections (endodontic therapy or extraction) Deep scaling and root planing in cases of disease Extraction of teeth with overall poor prognosis Dental prophylaxis Pre-transplant Dental Screening and Clearance All necessary dental treatment, and in particular extractions or other invasive procedures requiring significant time for healing, should be completed at least two weeks before transplantation Orthodontic appliances and space maintainers can be left in place if non-irritating and if the patient is maintaining adequate oral hygiene Post-transplant Dental Care Elective dental care is generally deferred during the immediate posttransplantation period due to profound immunosuppression and risk for infection Dental management of the patient post-transplantation can be divided into 3 phases 1.Immediate post-transplant period 2.Stable graft period 3.Chronic rejection period (onset of GVHD in HCT) Post-transplant Dental Care Once the graft is stable and functioning and any acute rejection reaction has been controlled, the patient is considered to be in the stable phase During this period, patients should receive routine dental care including regular periodontal maintenance visits and active management of any evident dental pathology During chronic rejection or actively treated GVHD, transplant recipients are again at significantly higher risk for infection Oral Complications and Manifestations Infectious and non-infectious oral complications may be encountered in organ transplant patients Patient evaluation begins with a comprehensive medical history, review of current medications, and assessment of pertinent laboratory results Physical evaluations include careful extraoral and intraoral examinations Additional tests may be indicated, like microbiological cultures, imaging, and tissue biopsy Management of oral complications depends on accurate and timely diagnosis, and perhaps careful coordination with the primary transplantation team Oral Mucositis Oral mucositis is a complication unique to HCT and related to both the intensive conditioning regimen as well as the course of methotrexate given for GVHD prophylaxis Typically develops 7-10 days following initiation of conditioning and does not resolve until engraftment and resolution of a normal white blood cell count Clinical features are characterized by diffuse, non-specific erythema and ulcerations of the non-keratinized oral mucosa, compromising oral function and quality of life Vitale, Marina & Modaffari, Carola & Decembrino, Ninni & Zhou, Feng & Zecca, Marco & Defabianis, Patrizia. (2017). Preliminary study in a new protocol for the treatment of oral mucositis in pediatric patients undergoing hematopoietic stem cell transplantation (HSCT) and chemotherapy (CT). Lasers in medical science. 32. 10.1007/s10103-017-2266-y. Medication-Related Oral Complications Aside from infectious complications, there are several potential oral complications associated with immunosuppressive medications used in transplantation Gingival Overgrowth Cyclosporine-associated gingival overgrowth is a well-described condition characterized by fibro-inflammatory enlargement of the gingiva Gingiva appears edematous, swollen and “overgrown,” often involving the interdental regions and extending into the crowns of teeth Management includes intensive periodontal care, improved oral hygiene, and surgery (gingivectomy) Tacrolimus is not associated with gingival overgrowth, and with the shift in use of tacrolimus over cyclosporine, gingival overgrowth is now infrequently encountered in this population Pyogenic Granuloma Tacrolimus has been associated with non-gingival soft tissue fibroinflammatory polyps, which closely resemble pyogenic granulomas Lesions present as exophytic ulcerated fibrous lobulated masses, measuring up to 3-4 cm Symptoms are variable and typically associated with secondary trauma, while the pathophysiological mechanisms and relationship with tacrolimus therapy remains unclear Management is simple surgical excision although some lesions may respond to intralesional steroid therapy mTOR Inhibitor-Associated Stomatitis mechanistic target of rapamycin (mTOR inhibitor) therapy with sirolimus and everolimus is associated with development of these painful aphthous-like oral ulcers Typically develop within the first few weeks of initiating therapy and tend to diminish with time, even without reducing or discontinuing sirolimus Management with topical and intralesional steroid therapy is generally effective, although in some cases mTOR inhibitor dose reduction may be considered Orofacial Granulomatosis-Like Lesions Atypical orofacial granulomatosislike oral lesions have been described in pediatric solid organ transplant recipients who received tacrolimus Features include multiple spherical nodules of the tongue, mucosal fissuring, and lip swelling Oral Hairy Leukoplakia This is a painless, benign condition that presents as corrugated white plaques on the ventrolateral tongue that can’t be removed It is associated with Epstein-Barr virus replication and encountered in patients with immunodeficiency Biopsy is diagnostic and demonstrates characteristic changes of EBV infection It is asymptomatic and does not require treatment Candidiasis Potential risk factors for development of oral candidiasis in transplant recipients include topical steroid use, salivary gland hypofunction, and use of removable oral prostheses Infection typically presents with generalized white curd - like papules and plaques throughout the oral cavity Some cases are purely erythematous, presenting with generalized or more patchy redness Candidiasis Diagnosis of candidiasis can typically be made clinically, but cytology or fungal culture may be helpful when there is uncertainty Systemic azole therapy with fluconazole is generally most effective Fluconazole therapy may lead to increased levels of these drugs and therefore require attentive monitoring or dosage adjustment Antifungal prophylaxis (e.g. fluconazole 100-200mg once weekly) is effective in cases of chronic recurrent infection Herpes Simplex Virus (HSV) The risk of HSV recrudescence is so high that all seropositive organ transplant recipients receive acyclovir prophylaxis during periods of profound immunosuppression Lesions present as very painful irregularly shaped shallow ulcerations that can affect both keratinized and non-keratinized surfaces, with the lips and tongue most frequently affected Management requires systemic antiviral therapy with acyclovir or valacyclovir, or rarely foscarnet in cases of acyclovir resistance Other Infrequent Infections Invasive fungal infection (most frequently aspergillus) may present intraorally, typically in the maxilla as an extension of sinopulmonary involvement This infection presents as an ulcerated mass and requires biopsy for diagnosis Cytomegalovirus reactivation rarely causes painful non-specific ulcerations that require biopsy and immunostaining for diagnosis Graft-versus-Host Disease GVHD is a major complication of allogeneic HCT and the leading cause of nonrelapse mortality With chronic GVHD, the oral cavity is one of the most frequently affected sites and can be a significant source of morbidity due to oral discomfort Clinical features include oral mucosal lichenoid inflammation with typical lichen planus-like changes, and associated mouth discomfort and sensitivity Graft-versus-Host Disease Other features include salivary gland dysfunction with xerostomia and high risk for dental decay and less frequently fibrosis of oral and perioral tissues leading to limited mobility and function Superficial mucoceles are a common feature characterized by superficial saliva filled blisters that develop primarily on the palate due to inflammation of minor salivary glands and do not generally require any specific therapy The lips are frequently affected, and while the hard palate is also frequently involved, lesions rarely extend to the soft palate or further posteriorly Graft-versus-Host Disease Management of oral chronic GVHD is directed at controlling symptoms and reducing risk of complications Oral mucosal disease can be effectively treated with topical steroids  The lips can be safely and effectively treated with topical tacrolimus ointment Prescription topical fluoride should be prescribed for patients with significant salivary gland dysfunction All patients should see a dentist for cleaning and routine dental radiographs 1-2 times per year Secondary Malignancy Organ transplant patients are at increased risk for developing cancer  Patients with hematologic malignancies who undergo HCT remain at risk for relapse of primary disease, typically within the first 1-2 years after transplantation  Extramedullary disease can present in the oral cavity as a non-specific mass or ulceration  Post-transplant lymphoproliferative disorders (PTLD) can similarly present in the oral cavity as a mass or ulceration Secondary Malignancy Risk of oral cavity and lip squamous cell carcinoma (SCC) is increased significantly in posttransplant patients, with patients with GVHD after HCT being at particularly high risk Management outcomes appear to be worse compared with nontransplant patients with oral SCC All transplant patients require annual oral cavity cancer screening Byun, June-Ho et al. “Squamous cell carcinoma of the tongue after bone marrow transplant and graft-versus-host disease: a case report and review of the literature.” Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons 66 1 (2008): 144-7 . References • Michael Glick (ed.); Martin S. Greenberg (ed.); Peter B. Lockhart (ed.); Stephen J. Challacombe (ed.). Burket's Oral Medicine. 13th edition. Wiley-Blackwell. June 2021. ISBN: 9781119597780