<div>Keywords: Graft-vs-Host disease, SARS-CoV2, COVID-19, Acute
lymphoblastic leukemia, Chronic myelomonocytic leukemia</div><div>To the Editor:</div><div>Graft-versus-host disease (GVHD) is a significant cause of morbidity and
mortality in patients receiving hematopoietic stem cell transplant
(HSCT), with a reported mortality rate as high as 50% in patients with
grade 3-4 GVHD.<sup>1</sup> The complex pathophysiology of GVHD
involves donor T cell activation and cytotoxicity against inflamed host
tissue.<sup>1,2</sup> There are many known risk factors such as
Human Leukocyte Antigen (HLA) mismatch, high cell dose, and history of
total body irradiation<sup>1,3</sup> Infectious triggers, such as
human herpesvirus-6 (HHV-6) and CMV reactivation are also well-reported
in literature, although the underlying mechanism is not
elucidated.<sup>4,5,6,7</sup> The authors share two pediatric
cases of acute GVHD exacerbation after SARS-CoV2 infection during the
post-transplant period. To date, there is limited literature regarding
sequelae of SARS-CoV2 infection in pediatric patients after
HSCT.<sup>8,9,10,11,12</sup> We aim to bring to light that
SARS-CoV2 infection (without COVID-19 disease) may be a potential
trigger for acute GVHD exacerbation.</div><div>Case #1:</div><div>Patient 1 is a 13-year-old male with history of very-high-risk
refractory Philadelphia-like B-cell acute lymphoblastic leukemia (ALL)
for which he received a haploidentical bone marrow transplant after
achieving complete remission one month prior to transplant. His
conditioning regimen consisted of fludarabine, total body irradiation,
and post-transplant cyclophosphamide. He engrafted sixteen days after
stem cell infusion, with negative MRD on bone marrow studies on day +30
and day +100. The patient’s GVHD prophylaxis included post-transplant
cyclophosphamide, mycophenolate mofetil, and tacrolimus. Soon after
engraftment, the patient developed grade 1 gut GVHD, which improved with
steroids and a single dose of basiliximab. Oral steroids were
successfully weaned off and the patient had a stable post-transplant
course with resolution of GI symptoms. On day +122, the patient tested
positive for SARS-CoV2 by RT-PCR of a nasopharyngeal swab, which was
obtained for pre-procedural screening. He remained asymptomatic and
subsequently did not receive any viral-directed therapy for immediate
sequelae of SARS-CoV2 infection.</div><div>However, about one month after testing positive for SARS-CoV2, the
patient developed worsening rash and diarrhea as well as hematochezia. A
full infectious workup was negative. Elevated biomarkers (ST2, Reg3α)
from an acute GVHD panel supported clinical diagnosis of late onset,
grade 4, acute lower gastrointestinal GVHD. He received IV
methylprednisolone, other immunomodulatory agents, as well as
extracorporeal photopheresis (ECP) for treatment of GI GVHD.
Unfortunately, he proceeded to develop GVHD of his liver, confirmed by
biopsy two months after onset of hyperbilirubinemia. By time of this
publication, this patient has passed away due to complications secondary
to GVHD.</div><div>Case #2:</div><div>Patient 2 is a 16-year-old female with history of treatment-associated
chronic myelomonocytic leukemia (CMML) that developed three years after
completing treatment for pre-B lymphoblastic lymphoma. The patient
received a matched related donor (MRD) bone marrow transplant after
completing myeloablative conditioning regimen consisting of busulfan and
cyclophosphamide. She engrafted seventeen days after stem cell infusion.
GVHD prophylaxis consisted of tacrolimus and methotrexate. There was no
concern for acute GVHD immediately after transplant. However, the
patient’s course was complicated by positive SARS-CoV2 detected by
RT-PCR on pre-procedural surveillance nasopharyngeal swab obtained 34
days post-transplant. Although the patient was asymptomatic, she was
treated with bamlanivimab (a monoclonal antibody for treatment of
COVID-19) due to her proximity from transplant. About three weeks after
testing positive for SARS-CoV2, the patient was noted to have exam
findings concerning for GVHD of her skin and upper GI tract, as well as
elevation in transaminases. She subsequently underwent a liver biopsy
which confirmed grade 2 GVHD of her liver. The patient was treated with
steroids as well as other immunomodulatory medications, with which
symptoms of GVHD improved. She is currently tolerating a wean in
immunosuppression without recurrence of her transaminitis.</div><div>Given the severity of symptoms and impact on long-term survival and
quality of life, it is important to recognize risk factors for early
recognition and treatment of GVHD. For known viral triggers such as
HHV-6 and CMV, patients are often started on prophylactic anti-viral
medication and monitored closely for viral reactivation. SARS-CoV2 is a
novel coronavirus that has rapidly spread across the world. To date,
there is no literature available describing long-term sequelae of
SARS-CoV2 infection in pediatric patients who have received HSCT. We
wanted to recognize the association observed in two cases of acute GVHD
exacerbation in patients who tested positive for SARS-CoV2 after HSCT.
Furthermore, we note that the second patient received SARS-CoV2-directed
therapy, after which she experienced a less severe course of GVHD.
Meanwhile, the first patient did not receive directed therapy and
subsequently required prolonged hospitalization to treat acute
exacerbation of skin and lower GI GVHD, as well as new onset liver GVHD.
He required use of multiple immunomodulatory agents in addition to
photopheresis and systemic corticosteroid therapy prior to his untimely
death.</div><div>The authors recognize that there are many confounding factors that
played a role in these two patients’ clinical course. Namely, the source
of HSCT- patient 1 received a haploidentical transplant while patient 2
received a MRD product. Historically, the incidence of grade II-IV acute
GVHD is lower in patients who received MRD HSCT compared to those who
received haploidentical HSCT (25-27% vs 20-80%).<sup>3,13</sup>However, recent data published since the development of post-transplant
cyclophosphamide regimens have shown a comparable incidence of grade
III-IV acute GVHD between the two groups (9.8 – 11% in MRD vs 0-11%
in haploidentical transplant).<sup>14,15.16,17</sup> The authors
recognize that there have been no head-to-head prospective studies in
pediatrics comparing GVHD incidence for MRD HSCT and haploidentical HSCT
with post-transplant cyclophosphamide. Therefore, it is difficult to
conclude whether the second patient’s lower baseline risk of GVHD or use
of SARS-CoV2 directed therapy contributed to the less severe course of
GVHD.</div><div>This possible association between SARS-CoV2 and development of severe
GVHD warrants further studies to identify long-term sequelae of
SARS-CoV2. If a strong correlation between SARS-CoV2 infection and acute
exacerbation or onset of GVHD is found, it may be beneficial for
post-transplant patients (symptomatic or not) to receive
SARS-CoV2-directed therapy to alleviate risk of steroid-refractory GVHD.</div><div>Conflict of Interest: The authors do not have any conflicts of interest
to disclose.</div><div>References:</div><div>1. Jamil MO, Mineishi S. State-of-the-art acute and chronic GVHD
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