Cover Story

Skin Disease in Solid Organ Transplant Recipients

February 2014

To view the Tables in this article, please download the pdf file.

Advances in immunosuppressive therapies have resulted in enhanced survival among organ transplant recipients (OTRs). As a result of a growing population of immunosuppressed patients with prolonged survival, it is imperative that the dermatologists recognize the consequences of long-term immunosuppression and provide appropriate clinical management. Modification of the immune system places OTRs at an increased risk for a number of cutaneous conditions, including side effects from the medications themselves, immune-mediated effects from the transplanted organ, opportunistic infections and malignancy.

Cutaneous Effects of Immunosuppressives

Adverse cutaneous events from immunosuppressive medications are common. A recent survey of 80 renal transplant recipients receiving sirolimus (Rapamune) found that 99% had some type of adverse cutaneous event with 25% experiencing a severe event.¹ Table 1 summarizes adverse events of commonly used immunosuppressive agents.

Cutaneous Effects of the Transplanted Organ

Most commonly associated with hematopoietic stem cell transplantation, acute graft versus host disease (GVHD) can also occur following solid organ transplantation. The highest occurrence of acute GVHD is after small intestine transplantation (5.6%), followed by liver transplantation (1%-2%).^2,3Risk factors for developing GVHD include donor human leukocyte antigen homozygosity, advanced age and inadequate or interrupted immunosuppression. GVHD often occurs between 2-6 weeks following transplantation.³ Skin involvement is often the first indicator of GVHD and precedes hepatic and gastrointestinal symptoms. Cutaneous findings typically involve erythematous macules and papules first presenting on the palms and soles that progresses to a morbilliform eruption and potentially a generalized erythema with desquamation. Presentation can be difficult to distinguish from a severe drug eruption and skin biopsy may be required to confirm the diagnosis.⁴ Treatment with biologics such as daclizumab (Zenapax), basiliximab (Simulect) or other immunosuppressive agents in addition to intravenous (IV) corticosteroids have been attempted with some success. However, mortality of GVHD in solid organ transplant patients is greater than 75%.⁵

Infectious Diseases of the Skin in OTRs

Immunosuppression required to maintain allograft function in OTRs results in an impairment of cell-mediated immunity, making these patients prone to a variety of cutaneous infections (Table 2). A review of 134 renal transplant recipients showed that 105/134 (78%) patients developed cutaneous infections, with the most frequent infections being dermatomycoses, herpes zoster and folliculitis.⁶ Both unusual presentations of infection with typical pathogens and infections with rare opportunistic pathogens can make diagnosis and management difficult. Infections may be a primary focus or representations of an underlying disseminated or systemic infection. Chronologically, skin infections show 3 phases in which different infections predominate.^7-10

In the first postoperative month, most infections are related to surgical complications and infections with nosocomial organisms. Wound infections, cellulitis and superficial pyodermas caused by Staphylococcus and Streptococcus are the most common cutaneous infections during this time period. Additionally, atypical pathogens including gram-negative bacteria, fungi and mycobacteria can cause soft tissue and wound infections in OTRs. Deep involvement of a primary cutaneous infection can result in necrotizing fasciitis or wound dehiscence and these cases must be evaluated thoroughly with a low threshold for treatment with IV antibiotics or referral for surgical debridement.

Reactivation of herpes simplex virus (HSV) occurs with an incidence of 15%-45% of OTRs, primarily within the first 3 postoperative weeks.^7,11-12 The most common manifestation of HSV in OTRs is orolabial and anogenital lesions, however, widespread dissemination may occur, which is associated with a high mortality.¹² Treatment for HSV includes acyclovir, valaciclovir and famciclovir. In the presence of acyclovir-resistant HSV, foscarnet, cidofovir and trifluridine are alternatives that have been successful in patients with AIDS, but clinical experience in OTRs is lacking.¹³

In the second through fifth post-operative month, continued immunosuppression leads to infections with opportunistic organisms such as Nocardia, Bartonella and atypical mycobacterial species. Nocardia, a gram-positive, acid-fast rod found in the soil, typically presents as primary pulmonary disease. Cutaneous involvement is typically secondary through traumatic inoculation through contact with soil; however, both dissemination and primary skin involvement can occur.¹⁴ Cutaneous nocardiosis can present as subcutaneous nodules with pustules, abscesses with sinus tract formation, ulcers, granulomas or lymphocutaneous infection. Treatment of choice for nocardiosis is trimethoprim-sulfamethoxazole; however, resistance to sulfonamides is increasing and patients may require treatment with imipenem (Primaxin I.V.) or amikacin (Amikin).

Infection by B henselae, an intracellular gram-negative rod, can cause both catscratch disease and bacillary angiomatosis in OTRs. Catscratch disease results from transmission of Bartonella from a feline vector, OTRs can present with the typical findings of an inoculated papule with proximal adenopathy accompanied by fever. If not promptly treated in OTRs, catscratch disease can result in systemic infection commonly affecting the liver (bacillary peliosis hepatis), heart, spleen, lymph nodes or central nervous system.^15,16

Bacillary angiomatosis is a vasculoproliferative disorder commonly seen in HIV patients, but has also been described in OTRs.¹⁷ Bacillary angiomatosis presents as violaceous cutaneous lesions, with dissemination affecting the liver, spleen and bone. Diagnosis of disseminated Bartonella infection may require multiple diagnostic studies including cultures, serology and histopathologic examination. Treatment of choice for Bartonella is erythromycin or doxyclycline plus rifampin.

Infections with the atypical mycobacteria, which include Mycobacterium marinum, M fortuitum, M abscessus, M kansasii, M chelonae, M haemophilum and M avium-intracellulare, have been increasing in OTRs over the past decade. The incidence of cutaneous infection in renal transplant recipients ranges from 0.16%-0.38%. However, this low incidence may be attributable to a lack of clinical suspicion among practitioners.¹⁸

The spectrum of cutaneous manifestations is diverse and ranges from plaques, to nodules to ulcers.^19,20 M marinum affects patients exposed to contaminated water such as a fish tank or swimming pool. The extremities are the most common site of infection (“fish tank finger”) with sporotrichoid spread to sites of lymphatic drainage. Infection with M marium is typically limited to the skin and lymph nodes, while the rapidly growing M fortuitum, M chelonei, M abscessus as well as M avium-intracellulare and M haemophilum can cause disseminated disease following primary cutaneous infection in OTRs, which can result in significant morbidity. Treatment is complex and dependent upon the infecting agent. Typically, a multi-drug regimen is employed with careful consideration to interactions with immunosuppressive medications.

Beyond 6 months of immunosuppression, there is an increased occurrence of infections with viral and fungal pathogens. Reactivation of varicella-zoster virus is common among OTRs. In a Canadian review, the overall incidence of herpes zoster following organ transplantation was 8.6%, with a median time of onset of 9 months.²¹ Among OTRs, there is a high rate of cutaneous scarring and postherpetic neuralgia as well the potential for dissemination involving multiple dermatomes and risk of reoccurrence. Herpes zoster should be treated with IV acyclovir, current research on the clinical application of varicella immunoglobulins in OTRs is lacking.²² Post-transplant vaccination with the varicella vaccine has been associated with disseminated disease after immunization and the safety and efficacy of the live viral vaccine in adults has not been adequately assessed.^23,24

Cytomegalovirus (CMV) is a significant cause of morbidity and mortality in OTRs. Infection may occur through a primary infection, reactivation of the latent virus or from donor transmission. Symptomatic infection occurs in 20%-60% of transplant patients, and cutaneous involvement is present in 10%-20% of patients and is associated with a poor prognosis.^13,25 Multiple skin morphologies of CMV infection have been reported, and none are pathognomonic. Definitive diagnosis of CMV relies on histological examination. Acute CMV infection is treated with IV ganciclovir.

Human papillomavirus (HPV) is a frequent cause of infection in OTRs, with an incidence ranging from 25%-50%.^26,27 HPV infection in OTRs has been linked to the development of periungual squamous cell carcinoma (SCC) as well as cancer of anogenital tract.^28,29 The evidence implicating HPV in the pathogenesis of SCC in immunosuppressed individuals is mixed. In a study by Arron et al, transcriptome sequencing of HPV in SCCs from immunosuppressed and immunocompetent patients showed an absence of HPV gene expression.³⁰ However, the possibility exists that HPV may play a role in the induction but not maintenance of cutaneous SCC.³¹ Treatment of warts caused by HPV involves use of conventional ablative therapies (cryotherapy, laser surgery, salicylic acid) and may also require intralesional bleomycin, cidofovir or topical imiquimod.^32,33 Topical imiquimod should be used on limited area and with caution in immunosuppressed patients. Immunotherapy with intralesional Candida or Trichophyton antigen has not been studied in OTRs, although a recent study showed efficacy in patients with HIV infection.³⁴ Administration of the HPV vaccine post-transplant is controversial, a recent study showed a suboptimal immune response among post-transplant patients but no adverse events.³⁵

Epidermodysplasia verruciformis (EV) is a rare genodermatosis associated with a susceptibility to HPV infection and subsequent HPV-mediated oncogenesis. Acquired disease has been described in patients with HIV as well as OTRs.^36-39 Clinically the disease presents as tinea versicolor-like hypopigmented macules or keratotic, flat, wart-like papules. There is no definitive treatment for EV. Topical glycolic acid,⁴⁰ imiquimod⁴¹and systemic retinoids and interferon⁴² have had limited success. A recent report of 6-month combination topical methyl aminolevulinate and photodynamic therapy followed by systemic retinoid was successful in 1 case of acquired EV in a patient with underlying myasthenia gravis.⁴³ Patients with EV must be closely monitored for development of skin cancer.

Molluscum contagiosum may affect both the adult and pediatric OTRs. Diagnosis is made based on the characteristic appearance of the centrally umbilicated keratinous plug. Molluscum may be more numerous, larger and refractory to treatment in OTRs.^44,45 Treatment with cryotherapy, curettage, electrodesiccation or imiquimod is recommended for cosmetically disturbing lesions.

Superficial fungal infections with dermatophytes, in addition to tinea versicolor and onychomycosis are very common among OTRs.⁴⁶ In a case control study of 102 consecutive renal transplant recipients, pityriasis versicolor was the most common fungal infection (36%), followed by candidiasis (25%) and onychomycosis (12%).⁴⁷ Infection by other opportunistic fungi such as Aspergillus, Cryptococcus, Zygomycetes, Histoplasma capsulatim, Blastomyces dermatitidis and Coccidioides immitis also can occur in OTRs and should warrant an investigation for systemic infection.⁴⁸ Cutaneous findings in fungal infections of OTRs are diverse and non-specific, diagnostics must include direct microscopy and culture of samples. Terbinafine, itraconazole and fluconazole has been found to be safe and effective in patients on immunosuppressives and HIV patients.^49-53 Griseofulvin and the azole antifungals should be avoided in patients on cyclosporine.^54,55

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Cutaneous Malignancy in Organ Transplant Recipients

The incidence and rate of recurrence, metastasis and death of cutaneous malignancy are increased in OTRs when compared to the general population (Table 3). Skin cancers affect more than half of OTR patients.⁵⁶ SCC is the most common cutaneous malignancy among OTRs, with a 65-fold increase in incidence compared to the general population.⁵⁷ SCC in OTRs is highly aggressive and associated with significant mortality. In a cohort of >1,000 OTRs, 9% of patients with SCC developed local or regional metastasis and SCC specific deaths accounted for 8% of the overall mortality.⁵⁸

Basal cell carcinoma (BCC) is the second most common malignancy, with a 10-fold increased risk.⁵⁹ The predominance of SCC as the most common subtype of skin cancer is reversed from the immunocompetent population, in which BCC is the most common.^57,60 The cause of carcinogenesis is multi-factorial in OTRs including impairment of immunosurveillance resulting in a reduced host response against tumor cells, oncogenic potential of immunosuppressant drugs, genetic risk factors and viral infections.^61-63

Identifiable risk factors for the development of SCC in OTRs include the duration of immunosuppression, with the risk of carcinogenesis increasing steadily with time post-transplant (Table 4).^60,64-66 Other well-defined risk factors include advanced age at time of transplant,^67-72 history of skin cancer prior to transplant,⁶³ history of sun exposure,^67-79 presence of actinic keratosis,^64,69 Fitzpatrick type I and II skin^{64,66,68-70,72} and a decreased CD4 count.⁷³ Some studies have shown that the presence of HPV infection, smoking and male sex are also risk factors for development of cancer but this has not been reproducible between studies.^{64,66,68,69,72-77} OTRs who develop non-melanoma skin cancer (NMSC) following induction of immunosuppression have a risk of almost 80% of developing a subsequent cancer, with a 52%-62% risk of developing a second cancer within 3 years.^78-81 Limited data has shown that among OTRs with dark skin, development of NMSC is much less common.^82-83

The type of allograft, thus the choice and level of immunosuppression are major determinants of the risk of NMSC development. The risk is greatest among simultaneous pancreas and kidney transplants, heart transplants and lowest among patients with liver transplants.^70,77,84-86

The degree of immunosuppression has been shown to positively correlate with the development of SCC. OTRs who were treated with a 3-drug regimen have been shown to develop NMSC at a rate 2-3 times higher than OTRs on a 2-drug regimen.^82,84 Another study found that the risk for SCC 3 years after transplantation correlated with the overall level of immunosuppression, rather than with a specific immunosuppressive drug.⁶⁹

Immunosuppression with mycophenolate mofetil and sirolimus have been associated with a lower risk of development of NMSC,^71,87-91 while azathioprine and cyclosporine have been associated with a higher risk and may be procarcinogenic through photosensitization.^{71,75,78,84,92-95} Switching from calcineurin inhibitors to sirolimus has been shown to decrease the risk of SCC but can be associated with significant adverse effects.^96-98

The management of NMSC in OTRs is dependent upon the type of cancer and its extent. Precancerous actinic keratosis progress more often and faster to invasive SCC in OTRs compared with the general population. For patients with a limited number of actinic keratosis, cryotherapy or curettage of individual lesions is the treatment of choice. Many OTR patients have a propensity to develop multiple lesions over a wide area, treatment options for these patients include topical 5-fluorouracil daily or under Unna boot occlusion (chemowrap),^99,100 diclofenac^101,102 or imiquimod.¹⁰³ Ingenol mebutate (Picato) was approved by the FDA in January 2012 for treatment of actinic keratosis; however, studies regarding use in OTRs as well as treatment and chemoprevention of SCC are lacking.^104,105 Photodynamic therapy with a topical photosensitizer has been shown to be more effective and cosmetically acceptable treatment for actinic keratosis in OTRs than 5-fluorouracil cream.^106,107 The aforementioned field therapies are best suited for the scalp and the face. Field treatment of the extremities often requires more aggressive or frequent therapies or 5-fluorouracil treatment under Unna boot occlusion. Biopsy of any lesions that persist following medical therapy is recommended.

Management of in situ and low-risk SCC is similar to that of the general population. These lesions can be treated with cryotherapy or electrodesiccation and curettage. Based on the revised 7th edition of the American Joint Committee on Cancer staging system, high risk features for SCC include: primary site ear or non-glabrous lip, Clark level IV, 2-mm thickness, >2 cm in greatest diameter, perineural invasion, poorly differentiated or undifferentiated, local recurrence, cranial, facial bone involvement or invasion of the skeleton.¹⁰⁸

In these high-risk lesions, surgical excision with histological examination through Mohs micrographic surgery is necessary. Patients with aggressive lesions may require adjuvant radiotherapy or chemotherapy.

Chemopreventive methods should be considered if the number of new SCCs exceeds 5-6 per year. Chemoprevention with oral acitretin has been shown to reduce the incidence of SCC and precancerous lesions in OTRs; however, poor patient tolerance and rebound after discontinuation limits the use of this medication.¹⁰⁹ Low-dose acitretin, however, is still considered to be very useful in treatment and prevention of eruptive keratoacanthomas. In our personal experience and in a published case series of 10 patients, low-dose oral capecitabine, the pro-drug of 5-fluorouracil, has been used with good results as a chemopreventive agent.¹¹⁰ Importantly, in our experience, discontinuation of capecitabine does not result in a rebound seen with acitretin.

OTRs are also at increased risk for cutaneous melanoma, with a 3-5 fold increased incidence compared to the general population.^56,111-112 Risk factors for melanoma in OTRs are similar to those in the general population including the presence of multiple nevi, family or personal history of melanoma and light skin. While OTRs with darker skin have a decreased risk for SCC, the risk of melanoma in African American OTRs was found to be 17 times greater than African Americans in the general population.¹¹² Current management of melanoma in OTRs is similar to that of the general population, with wide local excision with margins based on depth. Patients with nodal or metastatic disease may benefit from reduction in immunosuppression.¹¹³ Overall, survival of OTR patients with melanoma is significantly worse than would be expected in immunocompetent patients, regardless of the Breslow thickness.¹¹⁴

Other malignant skin tumors affecting OTRs include Kaposi’s sarcoma and Merkel cell carcinoma (MCC). Kaposi’s sarcoma affects between 0.2%-11% of renal transplant recipients, with an increased risk of cutaneous dissemination and visceral spread compared to the general population.^115-117 The risk of mortality from Kaposi’s sarcoma is related to the extent of the lesions at presentation.

Treatment includes discontinuation of immunosuppressive therapy or changing the treatment regimen to include sirolimus.¹¹⁸ Imiquimod, interferon alpha and chemotherapy have also been used for treatment of Kaposi’s sarcoma with varying degrees of success.^119-120 MCC, or primary neuroendocrine carcinoma of the skin, is a rare tumor with an aggressive course. The incidence of MCC among OTRs is >10 times the general population.^121-123 MCC has a varying presentation but most commonly presents as a blue or red, firm, non-tender, solitary, dome-shaped nodule with rapid growth on the head/neck or extremities.¹²⁴ Initial treatment of primary MCC is surgical excision with sentinel lymph node biopsy followed by adjuvant chemotherapy or radiotherapy.¹²⁴

All OTRs should be advised to avoid sun exposure, to protect exposed areas with sunscreen or clothing and regularly receive full mucocutaneous skin examinations. If possible, patients should be seen prior to transplantation for identification and management of any pre-existing lesions. Surveillance intervals of OTRs in dermatology clinics should be based on overall risk (Table 5).^66,125-127

Dr. Maley is with the Medical College of Wisconsin, Department of Dermatology in Milwaukee, WI.

Dr. Olasz is with the Medical College of Wisconsin, Department of Dermatology, in Milwaukee, WI.

Disclosure: The authors have no financial relationships that may lead to a conflict of interest. Funding for this study was obtained exclusively through departmental support.

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