Cutaneous Complications in Recipients of Lung Transplants

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Cutaneous Complications in Recipients of Lung Transplants A Pictorial Review Vickram Tejwani, MD; Himanshu Deshwal, MD; Byron Ho, MD; Manisha J. Loss, MD; Robin K. Avery, MD; and Atul C. Mehta, MD

Lung transplant is now an established modality for a broad spectrum of end-stage pulmonary diseases. According to the International Society for Heart and Lung Transplantation Registry, more than 50,000 lung transplants have been performed worldwide, with nearly 11,000 recipients of lung transplants alive in the United States. With the increasing use of lung transplant, pulmonologists must be cognizant of the common as well as the unique posttransplant dermatologic complications. Immunosuppression, infections, and a variety of medications and environmental exposures can contribute to these complications. This review aims to provide representative pictures and describe the pathogenesis, epidemiologic characteristics, and clinical manifestations of dermatologic complications encountered among recipients of lung transplants. KEY WORDS:

CHEST 2019; 155(1):178-193

dermatology; lung transplant; transplants

Lung transplant (LTx) is an established modality for a broad spectrum of end-stage pulmonary diseases.1 According to the International Society for Heart and Lung Transplantation Registry, more than 50,000 LTxs have been performed worldwide, with nearly 11,000 lung transplant recipients (LTRs) alive in the United States.1 With the increasing frequency of LTx, pulmonologists must be cognizant of the common as well as the unique posttransplant dermatologic complications. Diagnosis of these conditions can be challenging and requires constant

ABBREVIATIONS: AK = actinic keratosis; AN = acanthosis nigricans; BCC = basal cell carcinoma; CMV = cytomegalovirus; EBV = EpsteinBarr virus; HHV = human herpesvirus; HSV = herpes simplex virus; KA = keratoacanthoma; KS = Kaposi sarcoma; KSHV = KS-associated herpesvirus; LTR = lung transplant recipient; LTx = lung transplant; MCC = Merkel cell carcinoma; MF = mycosis fungoides; MM = malignant melanoma; mTOR = mammalian target of rapamycin; PTLD = posttransplant lymphoproliferative disorder; Sca = Scedosporium; SOTR = solid organ transplant recipient; SPF = sun protection factor; UV = ultraviolet; VZV = varicella zoster virus AFFILIATIONS: From Pulmonary and Critical Care (Dr Tejwani), Dermatology (Drs Ho and Loss), and the Division of Infectious Disease

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vigilance. This review aims to describe the pathogenesis, epidemiologic characteristics, and clinical manifestations of dermatologic complications after LTx. Most complications after LTx are related to immunosuppression and can be classified as neoplastic, infectious, iatrogenic, or miscellaneous (Table 1).

Neoplasms Cutaneous malignancies constitute approximately 95% of all malignancies that arise in solid organ transplant recipients (SOTRs).2 Immunosuppressants play a

(Dr Avery), Johns Hopkins Hospital and Health System, Baltimore, MD; and Internal Medicine (Dr Deshwal) and the Respiratory Institute (Dr Mehta), Cleveland Clinic, Cleveland, OH. CORRESPONDENCE TO: Vickram Tejwani, MD, Pulmonary and Critical Care, Johns Hopkins Hospital and Health System, 1830 E. Monument St, 5th Floor Baltimore, MD 21205; e-mail: [email protected] Copyright Ó 2018 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved. DOI: https://doi.org/10.1016/j.chest.2018.08.1060

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substantial role in increasing malignancy risk via direct carcinogenesis and immune surveillance reduction, allowing for the proliferation of atypical cells and oncogenic viruses.3 The immunosuppressants that impair T lymphocytes, natural killer cells, dendritic cells, and other antigenpresenting cells disrupt immune surveillance. The subsequent microenvironment is conducive to the growth of neoplastic cells, some of which may originate either from the donor organs or from the primary tumor development and reactivation. Similar to its effects in hosts who are immunocompetent, ultraviolet (UV) B radiation induces mutagenic photoproducts, especially in tumor suppressor genes and oncogenes among LTRs. Mutations in the p53 gene are enhanced further by immunosuppressants.4 Lower Fitzpatrick skin types are more susceptible to UV radiation damage. This environment promotes development of sun-induced neoplasms such as squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), as well as virus-induced neoplasms such as Epstein-Barr virus (EBV)-mediated posttransplant lymphoproliferative disorder (PTLD), Kaposi sarcoma (KS)-associated herpesvirus (KSHV)mediated KS, and human papillomavirus-mediated SCC.5 Keratinocyte Carcinomas

SOTRs are at 65- to 250-fold increased risk of skin cancers and their precursors.6,7 In a study involving 142 individuals including 16 LTRs, 57 (40.1%) developed malignant or precancerous skin lesions, including 25 with actinic keratosis (AK).8 In another study, the incidence of premalignant lesions including AK was 21%, and mean time to the development was 15.2 years from the transplant.9 The incidence and the number of lesions increased with time from transplant.

Figure 1 – Photodamage and mild actinic keratosis on the arm. (The patient provided verbal consent for the use of this photograph.)

Thirty-eight percent to 40% of cutaneous horns are AK.11 However, atrophic AKs are erythematous macules without scaling. Pigmented AKs manifest as pigmented scaly papules. AK also can involve mucosal tissue such as the lips (actinic cheilitis) or conjunctiva (conjunctival AK).12 People who are at a higher risk of developing precancerous lesions should be evaluated thoroughly and routinely for early diagnosis and care.13 The daily use of sunscreens with broad-spectrum sun protection factor (SPF) is recommended in all SOTRs because UV light is a highly prevalent risk factor.8 Squamous Cell Carcinoma

The pathogenesis of SCC in SOTRs is multifactorial. Similar to its effects in the general population, UV radiation leads to local and systemic immunosuppression that predisposes these individuals

Actinic Keratosis

AK is a premalignant skin lesion associated with sun exposure. UV radiation damages keratinocytes, resulting in their abnormal proliferation and the formation of AK.10 There is a progression that starts with field cancerization, development of AK, and then potentially transformation to SCC (Figs 1-3). AK has a diverse manifestation. Classic AKs are large, scaly, erythematous, thin papules, whereas hypertrophic AK is a much thicker lesion. AKs manifesting with cutaneous horns (cornu cutaneum) are hypertrophic lesions that have a projection with a height of at least one-half of their diameter with an erythematous base.

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Figure 2 – Photodamage and severe actinic keratosis. (The patient provided verbal consent for the use of this photograph.)

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Figure 3 – Voriconazole-induced phototoxicity. (The patient provided verbal consent for the use of this photograph.)

to SCC.14 Furthermore, immunosuppressants lead to proliferation of oncogenic viruses, which is substantiated by the finding that SOTRs have a higher human papillomavirus prevalence rate of up to 90% in cutaneous SCC compared with the rate in those with healthy skin (11%-32%).15 Additionally, immunosuppressants have a direct tumor-promoting effect. More specifically, they inhibit the calcineurinnuclear factor of the activated T-cell pathway, causing induction of activating transcription factor 3, a member of the enlarged activator protein 1 family, which plays a vital role in suppressing p53-mediated cell death and results in carcinogenesis.3,16 In particular, cyclosporine can cause resistance to UV-induced apoptosis in keratinocytes and may promote tumor growth and invasion by inducing the production of growth factors.17,18 Conversely, tacrolimus, which has been shown clinically to be associated with a lower relative risk of skin cancer than is cyclosporine, does not confer resistance to apoptosis in UV-exposed keratinocytes.19,20 Azathioprine also sensitizes cells to UV-induced damage through the incorporation of a metabolite into DNA that generates reactive oxygen species. Also, SOTRs receiving azathioprine have more frequent mutations in the p53 and TP53 genes than do patients with keratinocyte carcinomas who are immunocompetent.21-23 Relative to the general population, recipients of transplants have an increased incidence of SCC.24 Retrospective studies have estimated the incidence of SCC to be 3.6% at 36 months and 26.5% at 10 years after transplant.25,26 Age, male sex, and prior history of skin cancer are associated with the development of posttransplant SCC.25-27 Commensurate with the

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Figure 4 – Squamous cell carcinoma in situ of the hand in a recipient of a lung transplant. (The patient provided written consent for the use of this photograph.)

association of increasing age, the time since transplant is also a potential risk.26 There are several variants of SCC, but they all often manifest within areas of chronic sun exposure and actinic damage.23 SCC in situ, also known as Bowen disease, is an intraepidermal carcinoma that appears as an irregularly shaped scaly erythematous plaque (Fig 4). AK and SCC in situ may progress to invasive SCC, which extends into the dermis and has a risk of metastasizing (Figs 5, 6). Invasive SCCs typically manifest as scaly erythematous nodules that may be ulcerated and are more likely to be painful and symptomatic than are SCCs in situ. They also may appear as cutaneous horns. Keratoacanthomas (KAs) are a variant of SCC; they are dome-shaped papules or nodules with a central keratin plug or ulceration. KAs may regress spontaneously, which is unpredictable, so these are treated in the same manner as is invasive SCC. The lesions can proliferate despite appropriate treatment. Multiple KAs also may manifest together, known as “eruptive KAs.” Examples of this include Grzybowski syndrome and drug-induced KAs.28 Basal Cell Carcinoma

Although BCC is more common than SCC in the general population, the incidence is comparatively low among recipients of transplants.24 A retrospective study has estimated the incidence of BCC to be 11.4% at 10 years after transplant.26 A population-based cohort study in Denmark showed BCC incidence of four per 1,000 person-years in the first 4 years after LTx.29 Compared with the expected incidence of skin cancers in the Danish population, the LTR population had a

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Figure 7 – Basal cell carcinoma of the right ear pinna. (The patient provided verbal consent for the use of this photograph.)

Figure 5 – Squamous cell carcinoma of the face in a recipient of a lung transplant. (The patient provided verbal consent for the use of this photograph.)

areas, with predominance on the face, upper chest, and back (Fig 7). Kaposi Sarcoma

4.1-fold increase in the incidence of BCC. A history of prior skin cancer increases the risk of posttransplant BCC.26 Superficial BCCs manifest as erythematous scaly macules and patches, whereas nodular BCCs typically manifest as pearly papules with or without ulceration and a rolled border. BCCs tend to affect sun-exposed

Figure 6 – Progression of squamous cell carcinoma of the face 5 months later in the same patient as in Figure 5. (The patient provided verbal consent for the use of this photograph.)

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KSs are tumors of endothelial cell origin associated with KSHV, also known as “human herpesvirus (HHV)-8.” KS typically develops through reactivation of KSHV when immunosuppression is initiated.30 Viral transmission also can occur during transplant through KSHV-infected donor-derived progenitor cells.31 The latter is supported by a French study in which 217 seronegative recipients of transplants received organs from KSHV-seropositive donors and approximately 30% seroconverted.30 Immunosuppression, especially with calcineurin inhibitors, predisposes patients to viral proliferation and, in this setting, the condition is considered an iatrogenic KS.3,32 Proliferation signal inhibitors, such as mammalian target of rapamycin (mTOR) inhibitors, are associated with a lower incidence of KS and, anecdotally, with lesion regression, which may result in favoring a transition to sirolimus when KS is diagnosed.32,33 KS typically involves the skin or the mucosa. Lesions are purplish, reddish blue, or dark brown-black macules; plaques; and nodules that may bleed and ulcerate easily. They may be disfiguring and can be associated with lymphedema, pain, and secondary infection (Figs 8, 9). KS in the posttransplant setting may be more diffuse in

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Figure 8 – Kaposi sarcoma with woody induration and violaceous papules. (The patient provided verbal consent for the use of this photograph.)

Figure 10 – Malignant melanoma of 1-mm Breslow thickness on the back. (The patient provided verbal consent for the use of this photograph.)

manifestation, often involving the face or trunk, lymph nodes, oral mucosa, and visceral organs.

like with other nonmelanoma skin malignancies, the risk of melanoma is associated positively with the duration and the intensity of immunosuppression.37 Transmission of melanoma from organ donors to recipients has been reported even after curative resection, raising the question of whether these patients are suitable organ donors.37-39 Male sex, increasing age, and azathioprine use also are associated with increased risk of melanoma.40

Malignant Melanoma

Various molecular mutations have been identified and targeted for treatment in malignant melanoma (MM). BRAF is a proto-oncogene that is a part of the mitogenactivated protein kinase pathway and promotes cell proliferation. Activating mutations such as BRAFV600E can result in uncontrolled cell growth and MM development.34 Upstream of BRAF, NRAS mutations exist in approximately 15% to 20% of metastatic melanomas.35 The melanocortin 1 receptor is protective against UV radiation and plays a critical role in determining skin pigmentation. In people with variant melanocortin 1 receptor, there is decreased melanin production, increased oxidative stress, and DNA damage, which may initiate development of MM (Figs 10, 11).34

Melanomas usually manifest as pigmented lesions and often are overlooked. Many systems have been developed to help identify melanomas clinically.41 One such method is the Glasgow 7-point checklist, which is based on physical examination (Tables 2, 3).42,43 Furthermore, most individuals’ pigmented nevi fit a specific profile. If there is a lesion that is visibly different

A 2015 meta-analysis suggests the pooled relative risk of melanoma in recipients of transplants is 2.71.36 Much

Figure 9 – Kaposi sarcoma of the right foot. (The patient provided verbal consent for the use of this photograph.)

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Figure 11 – Local cutaneous metastatic melanoma in a recipient of a renal transplant. (The patient provided written consent for the use of this photograph.)

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TABLE 1

] Cutaneous Complications in Recipients of Lung Transplants

Neoplasm Actinic keratosis Squamous cell carcinoma

TABLE 3

] Glasgow Weighted 7-Point Checklista

Major Criteria (2 Points)

Minor Criteria (1 Point)

Change in color

Size > 7 mm

Change in size

Sensory change in the lesion

Change in shape

Basal cell carcinoma

Crusting or bleeding Inflammation

Kaposi sarcoma Melanoma Merkel cell carcinoma

Adapted from Walter et al.43 a A score $ 3 suggests referral to dermatologist.

Posttransplant lymphoproliferative disorder Infection Varicella zoster virus Cryptococcus neoformans Blastomyces dermatitidis Pseudallescheria boydii Drug reaction Voriconazole-induced photosensitivity Amiodarone-induced skin toxicity Everolimus-induced petechiae Miscellaneous Acanthosis nigricans

transplant, with the highest incidence being at 10 years after transplant. Male sex; no induction therapy; or induction therapy not including a monoclonal antibody, mTOR inhibitor use, and renal transplant were associated with a higher incidence compared with otherwise.46 MCC usually manifests as a rapidly growing irregular firm nodule in a sun-exposed area. The most common sites for MCC are the head and neck area followed by the upper extremities. They may be violaceous to red in color and may ulcerate.47,48 Cutaneous PTLDs

from the rest of the nevi, then a melanoma should be suspected, even if it does not fulfill the ABCDE criteria.44 Merkel Cell Carcinoma

Merkel cell carcinoma (MCC) is an uncommon skin tumor of neuroendocrine origin. Merkel cell polyomavirus infection and integration of its genome have been identified in MCC tumor cells. This finding suggests possible integration before the clonal expansion of tumor cells and a potential role of Merkel cell polyomavirus in development of MCC.45 The standardized incidence ratio of MCC was 23.8 in a large population-based study of SOTRs compared with the general population, though the overall incidence was still low at 12.8 per 100,000 person-years.46 The incidence increases with age at transplant and time since TABLE 2

] ABCDE Technique of Diagnosing Melanomaa

ABCDE technique

PTLDs are classified by the World Health Organization into four major subtypes: early lesions (reactive plasmacytic hyperplasia, infectious mononucleosis-like PTLD), polymorphic (polyclonal, monoclonal), monomorphic (B-cell and T-cell lymphomas), and others (Hodgkin disease-like, plasmacytoma like).49 PTLD incidence in LTRs is 2% to 10%, two times higher than in other SOTRs.50,51 According to the Cincinnati Transplant Tumor Registry, 86% of PTLDs belonged to B-cell lineage and 14% to T-cell lineage; it also suggested that extranodal manifestation is common in PTLDs with the involvement of the lungs, CNS, and gastrointestinal tract.41 TABLE 4

] Recommendations for Recipients of Solid Organ Transplants144,145

Recommendations 1. Use sunscreen daily with sun protection factor 30 and wear tightly woven protective clothing, including longsleeved shirts, pants, broad-brimmed hats, and sunglasses.

C: Color variegation

2. Perform self-examinations of the skin and visit the dermatologist; a thorough self-examination should be taught to the patient during initial visits to identify any new lesions or changes in existing lesions.

D: Diameter > 6 mm

3. Seek early treatment for suspicious-looking lesions.

E: Evolution of lesions

4. Use preventive strategies such as topical creams, oral medications, and skin treatments, which potentially can reverse precancerous lesions.

A: Asymmetry B: Border irregularities

42

Adapted from Abbasi et al. This serves as an indication for a skin biopsy.

a

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Primary cutaneous PTLD is a rare entity and consists mainly of T-cell lymphomas and B-cell lymphomas without extracutaneous manifestations at the time of diagnosis.52 Mycosis fungoides (MF) is the most common primary cutaneous T-cell lymphoma among SOTRs; primary cutaneous CD30þ lymphoproliferative disorders are the second most common subtype of cutaneous T-cell lymphoma (37.5% of all cutaneous T-cell lymphomas).53 EBVassociated B-cell lymphoproliferative disorders are the most common cutaneous B-cell PTLD (90.9% of all B-cell PTLDs).54 There are multiple risk factors for the development of PTLD. EBV-associated B-cell PTLD typically develops within the first year after transplant, whereas EBVnegative PTLD generally develops in later years. Lympholytic and calcineurin inhibitors also increase the risk of cutaneous PTLD. Young adults are four times more likely to develop PTLD, whereas primary cutaneous PTLDs (both T-cell and B-cell PTLDs) are more common in men.53 Primary cutaneous B-cell lymphomas have a wide variety of manifestations but are most often red or purple nodules and plaques with or without ulcerations. They are usually asymptomatic and discovered incidentally but sometimes may be painful. They also can appear as an erythematous morbilliform eruption or, rarely, erythroderma.54,55 Lesions may be singular or widespread, commonly involving the extremities.56 Mucosal involvement may manifest as erythematous gingival hyperplasia or progressive necrotic ulcerations.57-59 Primary cutaneous T-cell PTLDs such as MF may manifest as pruritic infiltrative papules or plaques, often with an eczematous appearance or even erythroderma.54 Any surface may be involved, including characteristic double-covered areas such as the buttocks.54 Folliculotropic MF can manifest as localized alopecia, comedo-like lesions, or infiltrative plaques. It is usually multifocal or disseminated. Similar to B-cell PTLDs, folliculotropic MF lesions are often asymptomatic but can be pruritic or tender.53

transplant into a seronegative host, resistance to antiviral prophylaxis, absence of antiviral prophylaxis, and coinfection of two different types of herpesviruses.60 Being lymphotropic, herpesviruses disseminate readily in immunocompromised hosts when cellular immunity is suppressed. During the lytic phase, active viral replication causes cell lysis, which manifests as vesicular lesions, as seen in the cold sores of herpes simplex virus (HSV) and herpes zoster. The immune response to the virus, as seen in hosts who are immunocompetent, may manifest as erythema multiforme, but this manifestation is less frequent in patients who have received organ transplants because of immunosuppression.60 Skin manifestations are seen most commonly in HSV-1, HSV-2, varicella zoster virus (VZV), HHV-6 (HHV-6A, HHV-6B), and KSHV.61 They also have an immunomodulatory effect that can increase susceptibility to multiple opportunistic infections.60 The seroprevalence of HSV-1 ranges between 50% to 80% in adult SOTRs.62 HSV-1 mainly manifests as orofacial lesions: grouped tender vesicles, gingivostomatitis, and keratoconjunctivitis. HSV-1 genital lesions also are being recognized increasingly. Severe infections can cause hepatitis, pneumonitis, and encephalitis, particularly during the first few weeks after the transplant (Figs 12, 13).60,63 Seroprevalence of HSV-2 infection is less common than is seroprevalence of HSV-1 infection:15% to 50% in adults.62 HSV-2 most often causes genital lesions, but cases of cutaneous lesions, gingivostomatitis, and keratoconjunctivitis are increasingly common.60

Infections Herpesvirus

All types of HHVs can cause disease in patients with LTx. Besides immunosuppression, other risk factors include reactivation of latent infection, seropositive

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Figure 12 – Herpes simplex virus infection of the abdominal wall. (The patient provided verbal consent for the use of this photograph.)

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Figure 13 – Herpes simplex virus infection of the upper thigh in a recipient of heart and lung transplants. (The patient provided written consent for the use of this photograph.)

HHV-6 has two serotypes: type A is common in adults, and type B is common in childhood and causes most reactivations in SOTRs. The rates of reactivation of the virus following organ transplant are 20% to 28%.64 Seroprevalence reaches 100% by the adulthood.64 HHV6 commonly reactivates soon after organ transplant and is often asymptomatic. However, reactivation may be associated with fever followed by a cutaneous eruption. The exanthem typically manifests on or after defervescence, starts on the trunk spreading outward, and lasts for only 24 to 48 hours. Individual lesions of the exanthema are erythematous macules and papules with a surrounding white halo. The HHV-6 enanthem consists of Nagayama spots, which are erythematous soft palatal papules. Uvula and palatoglossal junction ulcers also may be seen. Reactivation in patients who are immunocompromised can be complicated by transplant rejection and other organ diseases.65 Higher rates of cytomegalovirus (CMV) coinfection also are observed in patients infected with HHV-6. Therefore, most clinical manifestations are due to CMV coinfections, but multiorgan involvement also can be seen in severe HHV-6 infection. HHV-6 has been found in the BAL of a recipient of heart and lung transplants, but its clinical importance is unclear.66 VZV is a member of the herpes family and a common pathogen, with more than 90% of the population having developed immunity through circulating anti-VZV antibodies.67 VZV primary infection manifests during childhood as chickenpox and reactivates as herpes zoster with advanced age, immunosuppression, and underlying malignancy.68 The rate of herpes zoster in SOTRs has been estimated to be between 3% and 25%.61,69

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Figure 14 – Herpes zoster infection. (The patient provided verbal consent for the use of this photograph.)

Retrospective studies looking at the rate of herpes zoster specifically in LTRs have estimated it to be 10% to 15%.70,71 Risk factors for herpes zoster in SOTRs include older age, thoracic transplant (vs abdominal transplant), and possibly mycophenolate-containing immunosuppressive regimens.69 Commensurate with findings in other studies in SOTRs, anti-CMV prophylaxis continues to demonstrate a protective effect against herpes zoster in LTRs.70,71 Herpes zoster is an eruption of unilateral erythematous papules in a dermatomal distribution that evolves into grouped vesicles or bullae and may become pustular. Lesions typically scab over in a week in hosts who are immunocompetent, indicating that they are no longer infectious (Fig 14). However, this process can be much more protracted in LTRs. About 26% of patients have postherpetic neuralgia.71 The incidence of facial involvement is 10.3%; however, the exact incidence of ocular involvement is unknown.70

Cryptococcus neoformans The overall incidence of Cryptococcus neoformans infection is estimated to be 2.8% in all SOTRs, with an attendant mortality rate of 42%.72 Skin involvement is typically a sign of disseminated infection. However, the rare entity of primary cutaneous cryptococcosis has been described.73,74 Primary cutaneous cryptococcosis can manifest as a nodule, ulceration, or cellulitis (Fig 15).75

Blastomyces dermatitidis Blastomyces dermatitidis is typically a pathogen of primary pulmonary origin with dissemination to other organs. Its manifestation as a primary dermatologic condition has been described; however, in some

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In a review of 23 case reports involving SOTRs, S apiospermum had an overall incidence of 0.1%.79 Three SOTRs had cutaneous manifestations, and eight had disseminated disease.79,80 Among these patients, two LTRs and one recipient of heart and lung transplants had an Sapiospermum infection.79 LTRs had a trend toward higher incidence of infection (P ¼ .06).79 Most Sca skin infections are subcutaneous, manifesting as mycetomas. They also can manifest as multiple nodules on the extensor surface of the upper extremities, pustular and ulcerating lesions, or occasionally as subcutaneous abscesses or lymphocutaneous lesions resembling sporotrichosis.81 In a review conducted in Japan, of 28 patients with cutaneous Sca, 20 (71.4%) had an upper and the rest had lower extremity involvement, most commonly affecting the exposed areas.82 Nocardiosis

Figure 15 – Cryptococcal cellulitis in a recipient of a solid organ transplant. (The patient provided verbal consent for the use of this photograph.)

instances, asymptomatic pulmonary involvement was identified with a subsequent CT scan.76 Skin blastomycosis has two different forms: a hyperkeratotic, exophytic lesion that mimics skin malignancy and a nodular erythematous to violaceous lesion that may coexist with pulmonary nodules.

Pseudallescheria boydii or Scedosporium apiospermum Pseudallescheria also known as “Scedosporium (Sca),” is a rare fungal infection that increasingly is being recognized as a life-threatening infection in hosts who are immunocompromised. The infection may be cutaneous, subcutaneous, or disseminated. It has been isolated in 8% of sputum samples from patients with cystic fibrosis, which puts them at high risk for colonization and invasive infection after LTx.77 In a patient who is immunocompetent, these species cause localized infections in the form of a chronic subcutaneous inflammation known as “mycetoma.” However, in the immunocompromised population, Sca infection may have many sequelae, including brain abscess (29%), lung abscess and fungal ball (49%), skin involvement (31%), and disseminated disease (46%).77,78

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Nocardiosis increasingly is being recognized among SOTRs, with an incidence of 0.7% to 3.5%.83-88 Husain et al86 found that it affects the native lung 75% of the time in patients with single LTx. Risk factors for nocardiosis include high-dose prednisone therapy during the past 6 months, treatment with lymphocytedepleting antibody in the previous 12 months, high level of calcineurin inhibitors in the previous 30 days, antifungal prophylaxis, and history of CMV disease.88 The pulmonary system and CNS commonly are affected by Nocardia, but disseminated disease and cutaneous manifestations can occur. Cutaneous infection occurs either by direct inoculation, such as penetrating trauma, or by hematogenous spread in disseminated disease. Primary cutaneous nocardiosis manifests as a lymphocutaneous syndrome-like sporothrix known as “sporotrichoid Nocardia.”89 It also can manifest as a mycetoma, cellulitis, or an abscess. It usually affects the lower extremities.90 Secondary cutaneous manifestations occur in disseminated disease and manifest as pustules, abscesses, and nodules.91 It can invade into deeper tissues, causing pyomyositis and osteomyelitis.89 Sporotrichosis

Sporotrichosis is a fungal infection caused by Sporothrix schenckii. It is a dimorphic fungus endemic in tropical and subtropical countries. However, it is a ubiquitous fungus that has been documented to cause human infection throughout the world.92 It commonly is found in soil and organic material. The most common route of infection is via either direct contact with soil or inhalation.92 However, it is also a zoonotic disease that

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can spread through scratches or bites from cats.93 S schenkii is known to cause infection of the skin and subcutaneous tissue but can be disseminated easily in hosts who are immunosuppressed.92,94 Sporotrichosis has a typical lymphocutaneous manifestation with multiple suppurative and granulomatous nodules, lymphangitic spread, and regional lymphadenopathy.94,95 It also can spread into deeper tissues and cause disseminated infection.94 Among LTRs, it may start with a primary pulmonary manifestation causing cavitary lesions and respiratory failure, often identified as donor-derived infection.96,97 Nontuberculous Mycobacteria

Nontuberculous mycobacteria infections are common in LTRs because of depressed cell-mediated immunity. The rate of lung infection among LTRs is 0.5% to 8%.98,99 Pulmonary disease is the most common manifestation of nontuberculous mycobacteria infection. Mycobacterium avium complex (MAC), Mycobacterium abscessus, Mycobacterium kansasii, and Mycobacterium xenopi are the most common pathogens.98 Cutaneous manifestation and disseminated disease are the next most common manifestations. Mycobacterium fortuitum, M abscessus, and Mycobacterium chelonae commonly cause localized skin infection. They manifest as papules, nodules, and granulomas with pigmented or purple discoloration.100 They may lead to recurrent abscesses and chronic draining sinuses.101 Mycobacterium marinum infection is caused by exposure to aquariums and infected water sources and commonly is known as “fish tank granuloma.”102 M abscessus commonly causes disseminated disease, especially if it colonizes the lungs before transplant in patients with cystic fibrosis.103

Iatrogenic Complications Voriconazole

Because the mortality associated with invasive fungal disease is high, antifungal prophylaxis strategies have been developed specific to different organisms. Current International Society for Heart and Lung Transplantation guidelines recommend either universal prophylaxis or targeted preemptive therapy, the latter based on the prior colonization and sequential fungal biomarkers detected in BAL fluid. Either strategy is acceptable, depending on the local epidemiologic characteristics and preference of the transplant center. In institutions that use universal prophylaxis,

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voriconazole for 6 months is the most common protocol, although posaconazole and itraconazole also have been used frequently.104-106 Voriconazole is a very effective triazole antifungal agent. However, it can have significant adverse effects, including, but not limited to, phototoxic cutaneous reactions. The incidence rate of dermal toxicity of voriconazole is 10% to 20%.107 The mechanism of reaction is thought to be inhibition of the P450 cytochrome system in the liver, which is responsible for metabolizing photosensitive substances such as retinol. Inhibition of this pathway leads to buildup of retinol under the skin, causing photosensitivity.108 Another hypothesis is that the metabolites of voriconazole produced by N-oxidation have retinol-like effect when exposed to sunlight.109 Because many drugs are metabolized via the P450 enzymes, there is a risk of an interaction with voriconazole and the potential for worsening the adverse effects. The cutaneous reactions are mostly idiosyncratic rather than dose dependent.110 However, the risk for skin cancer may be dose dependent.111 The clinical manifestation of cutaneous adverse effects is very diverse and includes cheilitis, photodistributed rash and hyperpigmentation, exfoliative dermatitis, discoid lupus erythematosus, and Steven Johnson syndrome.112 Other serious cutaneous complications such as bullous toxicity and pseudoporphyria also have been reported.113 Studies have suggested a hazard ratio of 2.6 for skin malignancies with long-term voriconazole use, especially in LTRs.111,114 Voriconazole has been associated with a higher incidence of SCC, although some larger studies and those that adjust for a broader number of confounding variables have not identified this association.25-27,115,116 There is typically a rapid resolution of symptoms on discontinuing the medication. However, if voriconazole cannot be discontinued, avoiding sun exposure and use of highSPF sunscreen reduces skin cancer risk.108,117-119 A thorough medical reconciliation also should be performed to see whether the drugs may interact with voriconazole or may themselves be associated with photosensitivity and may potentiate the cutaneous adverse effects. mTOR Inhibitors

Sirolimus belongs to the class of mTOR inhibitors. This class of drugs inhibits the mTOR pathway, thereby halting DNA and protein synthesis of T cells, B cells, and natural killer cells. Everolimus is a derivative of

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sirolimus. The mTOR inhibitors are associated with many cutaneous adverse effects. The most common mucocutaneous adverse effect is stomatitis that resembles aphthous ulcers. It can be severe enough to cause discontinuation or dose reduction in therapy.120 Other cutaneous adverse effects include acneiform eruptions, poor wound healing, and lower extremity edema (Figs 16, 17). In a trial of everolimus as a therapy for solid organ tumors, 48% of patients developed a morbilliform, eczematous, or acneiform skin rash.121,122 The rash most commonly involves the neck, face, and scalp and typically manifests within a few weeks after initiation of therapy. In a prospective study of SOTRs receiving sirolimus, an acneiform eruption occurred in 46% of participants and scalp folliculitis in 26%.123 Pilosebaceous diseases were more frequent in men, whereas hidradenitis suppurativa, which occurred in 12% of patients, was not sex dependent, but the mechanism is unknown.123 Poor wound healing has been observed in patients receiving the mTOR inhibitor sirolimus. A retrospective study of SOTRs receiving sirolimus demonstrated a 43.2% wound complication rate compared with 2.4% in those receiving a mycophenolate-based regimen.122,124 In a prospective study comparing patients receiving a sirolimus-based regimen with those receiving a tacrolimus-based regimen, wound complications occurred in 47% vs 8% of patients.125 The only other independent correlate of poor wound healing in that study was BMI. The proposed mechanism is an inhibitory effect of sirolimus on fibroblasts and endothelial cells. This effect has been demonstrated

Figure 16 – Lower extremity edema associated with mammalian target of rapamycin inhibitor. (The patient provided verbal consent for the use of this photograph.)

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Figure 17 – Lower extremity edema associated with mammalian target of rapamycin inhibitor. (The patient provided verbal consent for the use of this photograph.)

in vitro in biopsy specimen tissue from LTRs and also is postulated to be the mechanism by which these medications mitigate the development of bronchiolitis obliterans syndrome.126 The principal preventive method for poor wound healing is to avoid concomitant risk factors such as obesity and steroid use. Calcineurin Inhibitors

The class of calcineurin inhibitors includes cyclosporine and tacrolimus. Cyclosporine has been associated with gingival hyperplasia, sebaceous hyperplasia, and hypertrichosis. Cyclosporine has been shown in vitro to stimulate human gingival keratinocyte growth, which may be a result of induction of growth factors and inhibition of apoptosis.127,128 Gingival hyperplasia typically occurs within 3 months after initiation of cyclosporine and has an estimated incidence of 30% to 50%.129 Beyond exposure to cyclosporine, gingivitis is associated with the development of gingival hyperplasia.130 Accordingly, limiting exposure to cyclosporine and promoting good oral hygiene are recommended for prevention. Once gingival hyperplasia occurs, transitioning from cyclosporine to tacrolimus has been associated with improvement.131 Another randomized trial demonstrated that azithromycin and oral hygiene produced a higher resolution of gingival hyperplasia than did oral hygiene alone.132 The mechanism by which cyclosporine induces sebaceous hyperplasia has yet to be elucidated (Fig 18). It typically occurs several years after the initiation of cyclosporine therapy and has a reported incidence ranging from 11% to 17%.133 To our knowledge, there is no known prevention beyond limiting exposure to

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dose-related complication occurring in 59% to 86% of patients.137

Miscellaneous Acanthosis Nigricans

Figure 18 – Cyclosporine-induced sebaceous neoplasm and squamous cell carcinoma. (The patient provided verbal consent for the use of this photograph.)

cyclosporine. Transitioning to tacrolimus is an option, although there are case reports of tacrolimus-associated eruptive sebaceous hyperplasia.134,135

Acanthosis nigricans (AN) rarely has been associated with organ transplant. There are case reports of AN occurring after renal as well as bone marrow transplant (Fig 20).138-140 There is one documented case report of AN occurring several months after LTx.140 In all these cases, extensive workup ruled out underlying endocrine disorders or malignancies. There was also a case report of AN occurring in a patient with interstitial lung disease that resolved on initiation of immunosuppression therapy for LTx.141 It is unclear whether the underlying disease process or long-term immunosuppression causes the development of AN. AN can affect the nape of the neck, axillary folds, umbilicus, groin, knees, elbows, periorbital area, and hands (tripe palms).142 It is usually a clinical diagnosis based on its characteristic location and hyperpigmented and velvety appearance (Fig 20).140

Cyclosporine also has been associated with the development of hypertrichosis (Fig 19). The mechanism relates to some effects on cytokine production, modulation of keratinocyte terminal differentiation markers, keratinocyte nuclear translocation, and apoptosis inhibition. These changes were identified in mice administered cyclosporine.136 The typical onset of hypertrichosis is within months after starting cyclosporine, and it is a

Figure 19 – Cyclosporine-induced hypertrichosis. (The patient provided written consent for the use of this photograph.)

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Figure 20 – Acanthosis nigricans in a recipient of a lung transplant.140 (The patient provided verbal consent for the use of this photograph.)

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Skin Surveillance and Prevention of Skin Cancer With the advent of newer immunosuppressant regimens, survival rates have improved markedly among LTRs. However, morbidity and complications also have increased. As discussed, incidences of cutaneous diseases and cancers are high among SOTRs.7 It is therefore imperative for transplant pulmonologists to incorporate counseling, treatment, and education about skin malignancies into their practice (Table 4). On a routine follow-up visit, the physician should inquire about practices related to sun exposure and prevention. Adequate education should be provided about appropriate clothing and use of high-SPF sunscreens. Education regarding proper application of sunscreen also is recommended. Many patients do not apply enough sunscreen, and the ears, temples, and lateral and posterior parts of the neck often are overlooked.143,144 Risk stratification and a routine visit to the dermatologist are also imperative to detect cutaneous malignancies. However, the timing of screening is still not clear and may need further studies to identify an optimal duration for screening.47 Nevertheless, once a skin ailment is detected among LTRs, they should be referred promptly to a transplant dermatologist for the confirmation of the diagnosis and appropriate treatment. The After Transplant-Reduce Incidence of Skin Cancer alliance is a useful resource to raise awareness and educate recipients of transplants about skin cancer to reduce the incidence and severity of the disease.145

Acknowledgments Author contributions: V. T. is the guarantor of the paper, taking responsibility for the integrity of the work as a whole, from inception to published article. V. T., H. D., and A. C. M. contributed to conceptualization. B. H. and M. J. L. contributed to obtaining pictures. V. T., H. D., B. H., M. J. L., R. K. A., A. C. M. contributed to writing (original draft, review, and editing). Financial/nonfinancial disclosures: The authors have reported to CHEST the following: R. K. A. is a site investigator on clinical trials funded by AiCuris, Astellas, Chimerix, Merck, Oxford Immunotec, and Shire. None declared (V. T., H. D., B. H., M. J. L., A. C. M.).

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