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encephalitis, retinitis. CMV has a predilection to infect the transplanted allograft
hence more likely causing symptoms and end-organ damage in the grafted
organ [45].
CMV infections most often occur 30days to 6months after transplantation,
as this is the time when immunosuppression tends to be maximal. In patients not
receiving CMV prophylaxis (duration depending on the type of transplanted
organ, patient and donor serostatus, and transplant center protocols), CMV infec-
tion typically occurs within 3months of transplantation. The onset of disease
may be delayed among patients receiving anti-CMV prophylaxis but also tends
to occur within 3–6months after completion of antiviral prophylaxis in CMV
donor positive/recipient negative solid organ transplant recipients [45].
Donor and recipient CMV serostatus prior to transplant is the most signicant
risk factor with the highest risk of infection occurring in CMV-seronegative
recipients of a CMV-seropositive donor organ. In solid organ transplant recipi-
ents, the most common site of tissue-invasive disease is the gastrointestinal tract,
potentially causing esophagitis, gastritis, enteritis, and/or colitis. Typical symp-
toms include abdominal pain, diarrhea, and fever, however, signs may be subtle,
such as dyspepsia. Co-infection with C. difcile or associations with inamma-
tory bowel disease can occur. CMV hepatitis, cholangitis, cholangiopathy, and
pancreatitis also occurs and may or may not have associated diarrhea [38].
In addition to causing direct symptoms and tissue-invasive disease, CMV infec-
tion can cause indirect effects such as allograft dysfunction or rejection and
increased susceptibility to other opportunistic infections and death. One study dem-
onstrated graft dysfunction in 1 of 6 patients with CMV-associated colitis [46].
• Norovirus. More than 90% of non-bacterial infectious diarrhea cases are due to
norovirus with outbreaks occurring year-round but most commonly during the
winter months. Transmission occurs via fecal-oral route, contact with contami-
nated surfaces or via inhalation of aerosols from vomitus. In immunocompetent
patients, norovirus tends to cause acute nausea, vomiting, and diarrhea lasting a
few days, however, either acute or chronic diarrhea can occur in solid organ
transplant recipients. Many solid organ transplant recipients with norovirus will
develop weight loss and acute renal failure due to volume depletion. SOT recipi-
ents frequently develop chronic viral shedding. This can be associated with pro-
longed, sometimes intermittent diarrhea and can result in renal insufciency and
increased morbidity [38].
• Parasitic causes of diarrhea in solid organ transplant recipients are less common
but important to consider especially when other etiologies are not identied.
Giardia and cryptosporidium are the most common parasites to cause infection.
If no diagnosis is made, then further investigation should be undertaken for more
unusual pathogens such as Microsporidia, Cystoisosopora, Cyclospora, and
other ova and parasites [38].
9 Common Syndromes intheAdult Solid Organ Transplant Recipient
278
Non-infectious causes:
• Drug induced. Drug-induced diarrhea in common in the solid organ transplant
recipient and may be due to the direct effects of the immunosuppressive drugs or
due to other medications commonly administered including antibiotics, colchi-
cine, or laxatives.
– Compared to other immunosuppressive medications, mycophenolate mofetil
(MMF) or mycophenolic acid (MPA) are more commonly associated with
gastrointestinal side effects including nausea, vomiting, and diarrhea [46, 47].
The diarrhea associated with MMF and MPA is dose-dependent due to direct
enterocyte damage. Diarrhea caused by mycophenolate is usually bothersome
but not severe; however, in some cases, dehydration, gastrointestinal hemor-
rhage or perforations can occur [48]. Additionally, a rarer disease similar to
inammatory bowel disease can occur.
– Calcineurin inhibitors such as tacrolimus or cyclosporine can cause diarrhea
due to their macrolide effects, which can increase gastrointestinal motil-
ity [38].
– Although less common, sirolimus and everolimus can also cause diarrhea.
– Non-immunosuppressive medications commonly used in solid organ trans-
plant recipients that are frequently implicated in causing diarrhea include
antibacterials, anti-arrhythmics, diabetic agents, laxatives, proton pump
inhibitors, and magnesium supplementation. A careful review for these medi-
cations with dose adjustments or discontinuation may be appropriate with the
guidance of the transplant team [38].
• Graft-Versus-Host-Disease (GVHD). GVHD is a multisystem disorder that
occurs when the immune cells transplanted from a non-identical donor (the graft)
recognize the transplant recipient (host) as foreign, thereby initiating an immune
reaction that causes disease in the transplant recipient. GVHD is most commonly
a complication of allogeneic hematopoietic cell transplant (HCT). It is a rare
complication in solid organ transplant recipients, generally only occurring in
liver and small intestine transplantation [38]. Acute GVHD usually occurs
between 2 and 6weeks after liver transplant however this can be variable with
late onset cases seen in other transplant settings [49]. (Small intestine transplan-
tation is not covered in this book). The clinical presentation of solid organ
transplant- associated GVHD includes skin rash, diarrhea, abdominal pain, gas-
trointestinal bleeding, fever, and in most cases quickly advances to become a
multisystem disease affecting the bone marrow and other non-transplanted
organs [38, 49]. The characteristic skin rash is red to violet maculopapular
lesions rst appearing on the hands and soles but may progress to the whole
body, coalesce and in severe cases lead to the development of vesicles or bullae.
The mortality rate of SOT-associated GVHD can exceed more than 75% [49].
Diagnosis is based on clinical symptoms, pathologic changes in biopsied tissues,
and systemic lymphoid chimerism.
K. O’Connor and C. J. Wong
279
• Post-Transplant Lymphoproliferative Disorder (PTLD). Post-transplant lympho-
proliferative disorder (PTLD) is an important malignancy to recognize in solid
organ transplant recipients. It is a lymphoproliferative disorder with varying sub-
types, often similar to B-cell lymphoma, and is associated with higher levels of
immunosuppression as well as unfavorable EBV serostatus (donor positive,
recipient negative).
PTLD can affect virtually any organ system and has a variable presentation.
Extranodal masses occur in more than half of the cases of PTLD and can involve
the gastrointestinal (GI) tract, lungs, skin, liver, central nervous system and the
allograft. When PTLD occurs extra-nodally the gastrointestinal system is most
commonly affected. Since PTLD can occur anywhere along the GI system,
symptoms may include chronic diarrhea, weight loss, protein-losing enteropathy,
abdominal pain and anorexia [38].
• Small intestine bacterial overgrowth (SIBO). Small intestine bacterial over-
growth may account for more than 10% of cases of chronic diarrhea in solid
organ transplant recipients. SIBO occurs when bacteria colonize the upper small
bowel leading to malabsorption and diarrhea. Immunosuppression, exocrine
pancreatic insufciency, achlorhydria, anatomic abnormalities (e.g., ileocecal
resection, blind loop syndrome) and small bowel motility disorders predispose to
SIBO.In many cases the etiology may be multifactorial. Patients may be asymp-
tomatic or symptoms can range from mild, mimicking irritable bowel syndrome
(abdominal pain or discomfort, bloating, cramping, atulence, chronic diarrhea),
to severe, resulting in steatorrhea, malabsorption and weight loss [50].
• Inammatory bowel disease (IBD). Inammatory bowel disease may occur de
novo in solid organ transplant recipients but more commonly it presents as an
exacerbation of pre-existing disease. De novo development of IBD is ten times
the incidence of IBD in the general population and is increased in CMV mis-
match patients (seropositive donor, seronegative recipient). Recurrent IBD fol-
lowing transplant appears to have a more aggressive course then de novo IBD
and many patients will require escalation in medical therapy or colectomy for
refractory disease. The risk of IBD recurrence post-transplant includes active
disease at the time of transplant, short duration of IBD prior to transplant and the
use of tacrolimus. Azathioprine and 5-aminosalicylates appear to be protective
[50, 51].
• Microscopic colitis. Either subtype—lymphocytic colitis or collagenous coli-
tis—can cause chronic watery diarrhea. In one study of kidney and kidney-
pancreas transplant patients, the incidence of microscopic colitis was 50-fold
higher in solid organ transplant recipients compared to the general population. A
denitive diagnosis requires histologic evaluation of large bowel biopsies [50].
• Malignancy. Colon cancer risk may be increased in solid organ transplant recipi-
ents and may rarely manifest as post-transplant diarrhea. Several studies have
demonstrated a 2–3-fold increased risk of colon cancer in transplant recipients.
Cancers may also develop at a younger age and behave more aggressively[50]
(See Chap. 10)
9 Common Syndromes intheAdult Solid Organ Transplant Recipient
280
9.4.1.5 Additional Testing andTreatment
Given the broad differential diagnosis, solid organ transplant recipients who present
with diarrhea require at least basic testing.
• The evaluation and management of patients admitted to the hospital is beyond
the scope of this book, but would typically include volume resuscitation, and an
expedited workup for infectious causes of diarrhea, often with consultation from
the transplant team and an infectious disease specialist; consultation with a gas-
troenterologist is indicated if endoscopy is required for a tissue diagnosis.
• In the stable patient, a workup is still recommended in almost all cases. This
practice is in contrast to the general population, many of whom have acute diar-
rhea and may be diagnosed clinically with a viral gastroenteritis and treated with
supportive care alone.
– Medications: it is recommended to stop any non-essential medications that
may be causing or worsening diarrhea. However, any potential changes in
immunosuppressants should be directed by the transplant specialist.
Medications are less likely to be causal if the diarrhea is acute and severe in
onset without recent medication changes; if there is associated nausea and
vomiting; if there is severe abdominal pain or signs of bleeding; or if there are
other signs of infection such as fever and chills.
– Acute diarrhea (< 14 days): Compared to immunocompetent patients, the
evaluation of diarrhea in solid organ transplant recipients should be performed
more expeditiously due to the risk of severe complications. For very acute
cases (e.g., 1–3days) in solid organ transplant recipients who are >6months
since transplant, evaluation for common bacterial pathogens, common viruses,
and C. difcile is indicated. A serum CMV PCR is also a reasonable initial
test as CMV colitis can occur late after transplantation, although this test by
itself does not conrm a diagnosis of CMV colitis. For acute diarrhea in the
7–14day period, it is additionally reasonable to consider early testing for
parasitic causes, depending on the results of the initial testing (if completed)
and exposure history. If available, a stool enteric pathogen PCR panel that
includes bacterial pathogens, C difcile, and common viruses is a useful ini-
tial assay in addition to the serum CMV PCR.If a stool enteric pathogen PCR
panel is not available, then bacterial and viral pathogens can be tested sepa-
rately from the Giardia antigen and ova and parasite testing. If the initial test-
ing is negative and the diarrhea persists, then consultation with a
gastroenterologist is indicated, as workup for CMV colitis via endoscopy, as
well as evaluation for other conditions, may be required.
– Persistent (14–30days) and chronic diarrhea (>30days): If the patient pres-
ents late in the course with prolonged diarrhea, then all testing for acute
causes should still be performed, although bacterial enteric pathogens become
less likely to be a cause. In solid organ transplant recipients, viruses such as
norovirus can lead to a chronic diarrhea not typical of immunocompetent
hosts. In addition, testing for parasitic causes should be performed. As men-
K. O’Connor and C. J. Wong
281
tioned above, a serum CMV PCR and a stool multi-assay for bacterial patho-
gens, viruses, C diff, and parasites is a reasonable rst step if available.
If the initial testing is negative, then consultation with a gastroenterologist
familiar with immunosuppressed patients is appropriate for consideration of
colonoscopy and possible upper endoscopy to evaluate for CMV infection,
inammatory bowel disease, microscopic colitis, and malignancy, depending
on the overall clinical suspicion. Note that the denitive diagnosis of CMV
infection requires biopsy for histopathology, and that the CMV viral load by
blood test can be negative but tissue gastrointestinal examination positive—
when uncertain, a transplant infectious disease specialist should be consulted.
• Treatment is directed at the underlying etiology if found. Empiric treatment (e.g.,
antibiotics) is generally discouraged in a stable patient, with preference to mak-
ing a correct diagnosis. Bismuth salts should be used with caution in SOT
because it is converted to salicylic acid and can result in toxicity among patients
with diminished renal function [52].
• If there is still no clear cause after the initial evaluation and the diarrhea persists,
the primary care provider should continue to work with the transplant team and
gastroenterology consultant, to consider adjustments in medications, and further
workup for malabsorption and less common causes of diarrhea. Empiric treat-
ment with anti-diarrheal medications is appropriate if infectious causes are ruled
out; some authors also recommend a trial of probiotics.
– Diarrhea may affect medication levels. For patients with chronic diarrhea, the
transplant team should be notied as they may check trough levels of immu-
nosuppressants more frequently.
• For a more detailed discussion of infectious causes, see Chap. 8.
9.4.2 Key Points
• As with all solid organ transplant recipients presenting with a new symptom, a
thorough history and directed exam should be performed.
• An early workup for infectious causes is generally indicated for solid organ
transplant recipients who present with diarrhea, especially if other infectious
symptoms are present and no obvious recent medication change was made.
• Infectious workup generally includes serum CMV PCR and stool tests for enteric
bacterial pathogens (more likely in acute diarrhea), C. difcile (any duration),
viruses (any duration), and parasitic causes (more likely persistent or chronic).
• Invasive testing with endoscopy may be required if initial testing is negative, or
to assess for CMV gastrointestinal disease and inammatory bowel disease.
• Consultation with a gastroenterologist and infectious disease specialist is often
indicated if initial workup is negative and to assist with prioritizing testing and
empiric treatment.
9 Common Syndromes intheAdult Solid Organ Transplant Recipient
282
9.5 Dermatologic Issues inSolid Organ
Transplant Recipients
Skin manifestations occur commonly in solid organ transplant recipients. The most
common occurrence is skin cancer. Infections, graft versus host disease, and cos-
metic complications of immunosuppressive agents should also be considered.
9.5.1 Malignancy
The risk of malignancy increases in solid organ transplant recipients due to the use
of long-term immunosuppressive therapies (see Chap. 10). The most common site
to develop malignancy is the skin, accounting for up to 40% of malignancies in solid
organ transplant recipients. Skin cancers in solid organ transplant recipients are
more aggressive, invasive, and metastatic compared to healthy controls [53]. A vari-
ety of factors increase the development of skin cancer, including intensity and dura-
tion of immunosuppression, skin pigmentation, sun exposure history, and geographic
location. More than 50% of skin cancers will develop in white solid organ transplant
recipients with rates of approximately 6% in nonwhite solid organ transplant recipi-
ents [54, 55]. Interestingly, as opposed to white patients, in nonwhite patients two-
thirds of these skin cancers develop in partial sun-exposed areas or sun-protected
areas including the genitals [56]. (Race is a social construct that is more compli-
cated than the binary categories white versus nonwhite; data is summarized this way
based on the reported data in the literature.)
Regular skin exams are important in the care of the solid organ transplant recipi-
ent. The frequency of skin examination may range from once yearly if there is no
history of skin cancer or actinic keratosis (AK) to every 3–6months in the setting of
nonmelanoma skin cancers, AKs, and melanomas. The recommended frequency of
skin exams varies depending upon risk factors, medical history, degree of immuno-
suppression, and history of skin cancer (including number and type of cancer).
Rapidly developing tumors, aggressive tumors or metastatic skin cancer requires
more frequent exams, usually every 4–6weeks. Skin cancer exams should also
include palpation of lymph nodes. Involvement of dermatologists in the care of
solid organ transplant recipients is frequently indicated. The use of chemopreven-
tion of skin cancer may be appropriate in some patients and should be guided by
dermatologists.
9.5.1.1 Nonmelanoma Skin Cancers (NMSC)
Nonmelanoma skin cancers including squamous cell carcinomas (SCC) and basal
cell carcinomas (BCC) occur the most often. However, solid organ transplant recipi-
ents are also at risk for melanoma and Kaposi sarcoma. As compared to the general
K. O’Connor and C. J. Wong
283
population in whom BCCs are more common, solid organ transplant recipients are
65–250 times more likely to develop SCC and 6 to 16 times more likely to develop
BCC [55, 57, 58]. As the time from transplant increases, the risk of skin cancer also
increases. Based on a large cohort of over 10,000 adult U.S. transplant recipients
who received their primary transplant in 2003 and were followed for a median time
of 6years, the predictors of post-transplant skin cancer included the following in
order of importance: white race, history of pre-transplant skin cancer, age at trans-
plantation ≥50years, male sex and thoracic organ transplant [59]. Several other
large studies found similar ndings and predictors for skin cancer [60, 61].
The proposed pathogenesis for higher rates of skin cancer in solid organ trans-
plant recipients includes the effects of immunosuppressive medications in reducing
immune surveillance and leading to the survival and proliferation of atypical cells;
direct or contributory carcinogenic effects of the calcineurin inhibitors such as aza-
thioprine and cyclosporine; or proliferation of oncogenic viruses [62]. Voriconazole,
a common antifungal medication used after lung transplantation, is associated with
increased photosensitivity and has been linked with the development of aggressive
SCC in immunocompromised patients [63, 64]. Several studies suggest that the
degree and duration of immunosuppression inuences the risk for NMSC, particu-
larly squamous cell cancers.
In patients with very little natural skin pigment, SCC most often develops in sun-
exposed areas. The development of SCC on non-sun-exposed areas is much less
common overall; however, the occurrence of SCC in sun-protected areas is the more
common distribution in patients with more pigmented skin. The development of
SCC within areas of chronic inammation and scarring is also more likely to occur
in patients with more pigmented skin. In addition to examining sun-exposed areas,
close inspection of the anus, genitalia and periungual areas (most often due to HPV
exposure), and sites of chronic inammation and scarring are important. SCC aris-
ing on the external ear or at mucocutaneous interfaces such as the lips, genitalia and
perianal areas tend to be more aggressive with rates of metastasis estimated to range
from 10% to 30% [65].
The typical description of a SCC in immunocompetent patients includes the
development of one or more red, scaly, well-demarcated supercial plaques. Lesions
may also be papular, nodular, skin-colored or pigmented, or present as a cutaneous
horn. The pigmented variant is more common in patients with more darkly pig-
mented skin. The appearance of SCC may change depending upon the location and
one should maintain a high level of suspicion when evaluating persistent skin
lesions.
Numerous SCC or actinic keratoses may develop in solid organ transplant recipi-
ents especially if they have light natural skin pigment and a history of extensive sun
exposure. The scalp and back of the hands are common sites for multiple SCC or
AKs. The incidence and mortality of SCC is increased in transplant patients. Solid
organ transplant recipients are also more likely to develop lip cancer [66]. Pain is
not a typical symptom of SCC, however, in solid organ transplant recipients, this
could indicate an invasive tumor which may be associated with increased overall
mortality [67].
9 Common Syndromes intheAdult Solid Organ Transplant Recipient
284
Nodular basal cell skin cancer is the most common type of BCC, however, there
are other subtypes of BCC including supercial, pigmented, and inltrating—
therefore high clinical suspicion is needed for BCC when not presenting in the more
familiar nodular manner. The typical presentation of nodular BCC in immunocom-
petent and solid organ transplant recipients is as a pearly papule(s) or nodule(s) with
rolled borders and overlying telangiectasias in sun-exposed areas. Ulceration and
focal pigmentation are often seen.
Shave, punch, or excisional biopsies may be used for the diagnosis of SCC or
BCC.Ideally biopsies should extend to at least the mid-reticular dermis in order to
allow for adequate evaluation of invasive disease. Once diagnosis is conrmed
referral to dermatology surgery for additional resection is often needed.
9.5.1.2 Melanoma
Melanoma risk is increased in solid organ transplant recipients. Based on informa-
tion from a large investigation conducted in the USA, the incidence of melanoma
increases sharply in the rst 4years after transplant before declining steadily. Risk
also increases with the intensity and duration of immunosuppression. Compared to
the general population the risk of melanoma is more than twofold higher in solid
organ transplant recipients with higher rates in kidney transplant recipients than in
liver or lung. Male sex, increasing age, and azathioprine maintenance therapy were
also associated with increased rates of melanoma [68]. These risk factors along with
the use of cyclosporine or sirolimus were conrmed by another large study in kid-
ney transplant recipients [69]. Transmission of melanoma from organ donors to
organ recipients has also been reported. Compared to non-transplanted patients,
melanoma-specic mortality is higher in transplant recipients even when stage and
treatment are taken into account [70].
Although melanoma is more common in patients with less skin pigment, the risk
of melanoma may still be increased in patients with more skin pigment with certain
solid organ transplants. Based on a large study of renal transplant patients, the
annual incidence of melanoma was 17 times greater in African-American transplant
recipients than in the African-American general population [71].
There are four main subtypes of melanoma: supercial spreading (most common
type), nodular melanoma, lentigo maligna melanoma, and acral lentiginous mela-
noma (the least common type). The appearance of the melanoma will vary based on
subtype but several features will be shared. Utilizing the rules of the ABCDEs when
evaluating pigmented lesions is helpful. These include Asymmetry of pigmented
lesions, irregularity of Borders, change or variegation of Color, large Diameter
(greater than 6mm), and Evolution. Ulceration and bleeding are generally late signs.
The majority of melanomas arise de novo, however, about 30% may arise from a
pre-existing nevus. Transmission of melanoma from organ donors to organ recipients
has also been reported [72]. Although most melanomas are pigmented some may
appear to lack or contain little pigment and are referred to as amelanotic melanoma.
When suspicion for melanoma is high, punch or excisional biopsy is recom-
mended. Sampling the entire lesion is recommended when possible. Ideally, the
K. O’Connor and C. J. Wong
285
biopsy should reach the subcutaneous fat plane. This provides enough depth of tis-
sue for the dermatopathologist to visualize the melanoma and provide accurate stag-
ing parameters that guide treatment decisions and prognosis.
9.5.1.3 Kaposi Sarcoma
Immunosuppression increases the risk of the herpes human virus-8(HHV-8)-associ-
ated Kaposi sarcoma (KS). Rates of KS are highest in males, patients with more
skin pigment and lung transplant recipients. KS develops rapidly after organ trans-
plantation with a mean interval of 13months [54].
KS lesions may be faint, red-purple macules, papules, plaques, tumors or nod-
ules (Fig.9.1). They are often oval and may form along the lines of skin cleavage.
In people with more pigmented skin, lesions may be more subtle and easy to miss,
identied by hues of red and purple on a darker background. Exam should include
assessment of local lymphadenopathy. Koebnerization (lesions occurring in areas of
trauma) can occur. Cutaneous and/or mucosal lesions occur approximately 90% of
the time. The most common areas of involvement are the trunk and central face,
especially the nose. Visceral involvement develops in 25% to 30% of kidney trans-
plant recipients and 50% of heart or liver transplant recipients. The most frequently
involved organs include the GI tract, lungs, and lymph nodes [54].
Punch or excisional skin biopsy is recommended for diagnosis and allows evalu-
ation of the dermis and subcutis.
Fig. 9.1 Kaposi Sarcoma
presenting as plaques in
the extremities in a kidney
transplant recipient.
Reprinted with permission
from: Raedemaeker J, etal.
(2019) [73]
9 Common Syndromes intheAdult Solid Organ Transplant Recipient
286
9.5.1.4 Merkel Cell Carcinoma (MCC)
The risk of developing this rare tumor of neuroendocrine origin is 24-fold higher in
SOT recipients with the highest incidence occurring 10 or more years after trans-
plant [74]. Based on a small case series, SOT recipients have a 3-to-12-fold increased
risk for MCC-specic death compared to immunocompetent patients [75, 76]. MCC
usually presents as a non-tender, rapidly growing, red or blue papule or nodule in a
sun-exposed area (Fig. 9.2). It is often misdiagnosed as a benign lesion (cyst,
lipoma, and pyogenic granuloma). Because MCC is an aggressive cancer that can
spread quicky, lymph nodes closest to the growth should also be evaluated and skin
biopsy performed as quickly as possible. Punch, shave, or excisional skin biopsy is
recommended for diagnosis.
9.5.2 Infection
Immunosuppression in the setting of solid organ transplantation predisposes patients
to the development of dermatologic infections. Etiology may be bacterial, myco-
bacterial, viral or fungal. Often patients will experience co-infections. Human
Fig. 9.2 Merkel cell
carcinoma presenting in an
extremity. Picture from:
Harms, P.W., Harms, K.L.,
Moore, P.S. etal. [77]
K. O’Connor and C. J. Wong