Accepted: 28 July 2017 DOI: 10.1111/petr.13046
CASE REPORT
Airway plaque presenting after alteration of immunosuppression in a pediatric patient remote from heart transplantation Thomas D. Ryan1
| Michael J. Absalon2 | Alessandro de Alarcon3 | Anita Gupta4 |
Anna L. Peters5 | Angela Lorts1 | Lara A. Danziger-Isakov6
| Clifford Chin1
1 The Heart Institute, Cincinnati Children’s Hospital, Cincinnati, OH, USA
Abstract
2
Success after solid organ transplantation is dependent on the proper balance of im-
Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital, Cincinnati, OH, USA 3
Division of Pediatric Otolaryngology, Cincinnati Children’s Hospital, Cincinnati, OH, USA 4
Division of Pathology and Laboratory Medicine, Cincinnati Children’s Hospital, Cincinnati, OH, USA 5 Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital, Cincinnati, OH, USA 6
munosuppression to prevent rejection of the allograft while limiting the risk of developing infections and malignancy. We present a 9-year-old girl, remote from transplant, who presented with airway plaque after a change in immunosuppression to include the mTOR inhibitor sirolimus. Differential diagnosis included direct medication side effect, infection, and neoplasia. KEYWORDS
airway, EBV, heart transplant, immunosuppression, mTOR inhibitor, post-transplant lymphoproliferative disorder
Division of Infectious Diseases, Cincinnati Children’s Hospital, Cincinnati, OH, USA Correspondence Thomas D. Ryan, Heart Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA. Email:
[email protected] 1 | INTRODUCTION
atresia with intact ventricular septum. Her post-transplant course was complicated by chronic eczema and psoriasis and calcineurin inhibitor
The cornerstone of a successful course after solid organ transplan-
nephropathy, but there was no significant history of allograft rejec-
tation comes in the form of immunosuppression to prevent rejection
tion. Her immunosuppression regimen consisted of tacrolimus (goal
of the allograft. However, a balance must be achieved that not only
range 8-10 ng/mL) and azathioprine.
guards against loss of the transplanted organ, but also reasonably lim-
Approximately 2 months prior to admission, the immunosuppres-
its the risk of developing infections and malignancy. Given their effects
sion regimen was changed to tacrolimus (goal range 2-4 ng/mL) and
on important biological pathways, commonly used immunosuppres-
the mTOR inhibitor sirolimus (goal range 6-8 ng/mL) for history of
sant medications additionally put patients at risk for a vast array of side
nephropathy. She was switched back to tacrolimus and azathioprine
effects that can manifest in a variety of forms.
1 week prior to admission for parental concern of persistent upper respiratory symptoms and fatigue. The patient’s history of immunosuppression is represented in Table 1. On the day of admission, she was
2 | CASE
seen by her pediatrician for mouth sores with resultant decreased oral
The patient is a 9-year-old female with a history of orthotopic heart transplantation at 4 weeks old for failed palliation of pulmonary Abbreviations: EBER, Epstein-Barr virus encoding region; mTOR, mammalian target of rapamycin; PTLD, post-transplant lymphoproliferative disorder.
Pediatric Transplantation. 2017;e13046. https://doi.org/10.1111/petr.13046
intake, fever, persistent cough, and a recent unintended weight loss of approximately 3.5 kg. Upon admission, the patient was found to have age appropriate and stable vital signs, with pertinent examination findings of dysphonia and white-yellow plaque on the right anterior pillar of the oropharynx. Given her recent change to mTOR inhibitor therapy
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© 2017 John Wiley & Sons A/S. | 1 of 4 Published by John Wiley & Sons Ltd
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RYAN et al.
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Day
Tacrolimus (goal 8-10 ng/mL)
0
7
−2
10.7
Tacrolimus (goal 2-4 ng/mL)
Sirolimus (goal 6-8 ng/mL)
yes yes
−15
3.8
12.1
−30
3.4
9.9
−57
4.6
9.9
4.1
11.4
−64
Azathioprine
−71
10.1
yes
−92
10.6
yes
−143
13.4
yes
−157
17.1
yes
−287
7.3
yes
−397
10.5
yes
(A)
(B)
T A B L E 1 Immunosuppression for approximately 1 y prior to admission
(C)
F I G U R E 1 Findings on microlaryngoscopy and esophogastroduodenoscopy/colonoscopy. Demonstrated in the oropharynx are a thick, yellow plaque that appeared necrotic on the posterior pharyngeal wall (A) and the left arytenoid (B). Biopsies taken from this region are shown in Figure 2. Findings in the GI tract included ulcers in the transverse colon with intervening normal colonic mucosa (arrows, C) and cobblestoning in the gastric antrum (arrows, D)
(D)
and development of mouth sores, concern for medication side effect
were CD20 and EBER positive (Figure 2). The tumor cells showed
was raised, as was infection in an immunocompromised patient.
lambda restriction. Subsequent esophagogastroduodenoscopy and
Bedside flexible fiberoptic examination was performed revealing
colonoscopy, indicated for bloody stool and disease staging, showed
significant plaques through the oropharynx and smaller lesions on the
that she also had mild thickening and furrowing of her esophagus,
larynx, including the base of the tongue and soft palate. In addition,
mild cobblestoning in the antrum of the stomach, and areas of ulcer-
there was inflammation of the post-cricoid region and mild narrowing
ation in the transverse colon. Biopsies of the transverse colon also
of the glottis with an otherwise patent airway (Figure 1). Biopsy of
demonstrated lesions with increased large EBV-positive plasmacytoid
the posterior pharyngeal wall initially demonstrated extensive necro-
lymphoid cells. The patient was diagnosed with EBV-associated PTLD
sis with mixed inflammation; numerous rods, cocci, and filamentous
involving the oropharynx, larynx, duodenum, and transverse colon.
bacteria were identified and ultimately identified as oral flora. No
Computed tomography scanning showed no evidence for involve-
fungal organisms were identified. A second deep mucosal biopsy with
ment of lymph nodes in the chest, abdomen, or pelvis. The disease
immunohistochemistry and in situ hybridization for EBER revealed
course correlated with an increase in blood EBV quantitative PCR
a dense dermal inflammatory infiltrate composed predominantly of
from 0 copies/μg DNA on all prior studies, to 1159 copies/μg DNA at
lymphoid cells with a few scattered larger atypical lymphocytes which
the time of diagnosis.
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F I G U R E 2 Polymorphic PTLD with lambda light chain restriction in pharyngeal wall biopsy. (A) Histology shows squamous mucosa and portions of skeletal muscle with a band of an inflammatory infiltrate (B) composed predominantly of lymphoid cells varying from small mature to intermediate and larger atypical forms (arrows). (C) CD3 (T-cell lymphoid marker) stains many scattered non-neoplastic small lymphocytes within the infiltrate; arrows highlight negative B lymphoid neoplastic cells. (D) The minority population of large transformed neoplastic cells are immunoreactive (brown) to CD20 (B-cell lymphoid marker), and positive for EBV in situ hybridization stain (EBER) (insert, blue cells). The tumor cells showed lambda restriction (not shown here)
Immunosuppression was decreased as the initial treatment for
azathioprine for the first 8 years after transplantation based on a fa-
PTLD in this patient. As such, azathioprine was discontinued and the
vorable rejection profile. One year prior to the events of this case, she
tacrolimus goal decreased to 4-6 ng/mL. Ulcerations in the larynx
was switched from cyclosporine to tacrolimus for gingival hyperplasia.
completely resolved within 1 month; however, reduction in immuno-
Two months prior, she was switched to tacrolimus and sirolimus for
suppression failed to lead to a complete response in duodenum and
renal dysfunction. Thus, one possible cause of the patient’s findings
colon. Based on persistent evidence for PTLD on follow-up gastro-
was side effect of the mTOR inhibitor, as dermatologic and mucosal
intestinal scopes, she was then treated with 4 weekly doses of ritux-
adverse events are well documented. These include dermatitis, which
imab, which resulted in clinical resolution of disease and blood EBV
was found in our patient although the history was long-standing, and
levels. Her cardiac examination remained reassuring without evidence
aphthous stomatitis, a new finding in this case.1 Some of the patient’s
of allograft rejection.
constitutional symptoms, including fever and myalgias, are also known
Since initial presentation, the patient has been maintained on tac-
side effects of mTOR inhibitors. Another consideration was infection,
rolimus as a single agent for prevention of allograft rejection, with per-
with the initial clinical suspicion being a fungal infection. In a study
sistently negative endomyocardial biopsies. Due to ongoing concerns
of 1854 patients from the Pediatric Heart Transplant Study, invasive
of an unspecified autoimmune disorder comprising enteritis, derma-
fungal infections constituted a small proportion of total infections at
titis, and nephrotic syndrome, she is frequently on steroid therapy as
~7%.2 The highest risk was in the first 6 months after transplant, in pa-
well. She was recently found to have elevated EBV in peripheral blood,
tients with a history of mechanical support or recent intubation, none
prompting CT scan that was positive for lymphadenopathy in inguinal,
of which applied to our patient.
axillary, supraclavicular, and mesenteric nodes. Follow-up biopsy of
Ultimately, the patient was diagnosed with PTLD involving the
an inguinal node demonstrated no evidence for malignancy or PTLD.
pharynx including larynx, as well as the gastrointestinal tract from
Follow-up esophagogastroduodenoscopy and colonoscopy was posi-
the esophagus to the colon. In pediatric heart transplant recipients,
tive only for mild inflammatory disease.
malignancy occurs in 4.7% of 5-year and 9.7% of 10-year survivors, with lymphoma constituting 94% and 96% of those cases,
3 | DISCUSSION
respectively.3 Presentation involves the head and neck in 25%-63% of cases, with a single report describing 39% for heart transplant patients. In all of the previous reports, PTLD in the airway was
The current case presents a varied differential for airway involve-
exceedingly rare.4–12
ment in a pediatric patient on broad immunosuppression status post-
The cause of the increase in EBV and ultimately PTLD in this case
heart transplantation 9 years prior. Although it is not our current
is not clear. Historical cyclosporine and tacrolimus levels were within
preferred regimen, the patient was maintained on cyclosporine and
goal for 9 years prior to sirolimus therapy, and tacrolimus remained
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within goal during the 2 months of sirolimus administration. While sirolimus was above goal range during the 2 months of use, there was no evidence for over- immunosuppression based on normal white blood cell and absolute neutrophil count. Higher sustained levels of immunosuppression might increase the risk of developing PTLD, and our patient was maintained at higher goal range. Our institution did not use other markers of immunosuppression, such as ImmuKnow, at the time of this case. Donor-recipient EBV mismatch, which was present in this case (negative recipient, positive donor), is another factor known to contribute to PTLD, although the risk was lower in infants.4 Lastly, the patient had persistent autoimmune disorder that was difficult to control, the contribution of which was unknown. It is also of interest to note that mTOR inhibitors are shown to inhibit proliferation of EBV-positive lymphomas13 and may function as therapy for PTLD in some cases.14 Following patients for PTLD should involve serial measurement of EBV in the peripheral blood. Values for intervention vary between centers, but in our patient, the increase from negative to positive seems to be more important than absolute value. Our case illustrates the importance of considering PTLD in pathology temporally associated with significant alterations in immunosuppression, rather than simply assuming the changes to be directly related to medication side effect alone. In addition, we propose that the gastrointestinal tract should be evaluated for involvement when PTLD in the upper airway is identified.
D ISCLOSURE STATE M E N T The authors declare no conflict of interests.
AUTHORS’ CONTRI BUTI O N S Thomas D. Ryan: Collected data and drafted the manuscript; Alessandro de Alarcon: Provided and interpreted photographs from flexible fiberoptic examination and involved in critical revision of the manuscript; Anita Gupta: Provided and interpreted photographs from microscopic examination and involved in critical revision of the manuscript; Anna L. Peters: Provided and interpreted photographs from esophagogastroduodenoscopy and colonoscopy and involved in critical revision of the manuscript; Michael J. Absalon, Angela Lorts, Lara A. Danziger-Isakov, and Clifford Chin: Provided clinical input and
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involved in critical revision of the manuscript; All authors: Approved the final version of the manuscript.
How to cite this article: Ryan TD, Absalon MJ, de Alarcon A, et al. Airway plaque presenting after alteration of immunosuppression in a pediatric patient remote from heart
O RCI D Thomas D. Ryan
transplantation. Pediatr Transplant. 2017;e13046. http://orcid.org/0000-0003-4237-576X
Lara A. Danziger-Isakov
http://orcid.org/0000-0002-5691-5221
https://doi.org/10.1111/petr.13046