The n e w e ng l a n d j o u r na l of m e dic i n e

C or r e sp ondence

ST2 and Endothelial Injury as a Link between GVHD

and Microangiopathy
To the Editor: Vander Lugt et al. (Aug. 8, 2013,
issue)1 report an association between elevated
levels of ST2 protein, a marker of endothelial
injury, at the time of diagnosis of graft-versus-
host disease (GVHD) and resistance to glucocor-
ticoid therapy among the recipients of hemato-
poietic stem-cell transplantation (HSCT). The
authors found a strong association between ST2
levels at day 14 after transplantation, a point
well before the onset of GVHD, and the rate of
death at 6 months among patients without a
relapse in disease, but the cause of increased
mortality was not clear. Transplant-associated
thrombotic microangiopathy (TA-TMA) is trig-
gered by endothelial injury leading to comple-
ment activation and further endothelial injury,
organ failure, and increased mortality.2 We have
reported an incidence of TA-TMA of 30% in a
prospective study of screening for clinical signs
of TA-TMA (including an elevation in lactate
dehydrogenase levels, the presence of schisto-
cytes, thrombocytopenia, decreased haptoglobin,
and microangiopathic anemia).2 Endothelial in-
jury also occurs in GVHD,3 and TA-TMA and
GVHD frequently overlap, with clinical evidence
of both processes.4 In addition, endothelial injury
is reported to be associated with glucocorticoid
resistance in GVHD.3,5
We measured ST2 in three nonoverlapping
cohorts of pediatric and young-adult HSCT recipi-
ents. (Additional details about the patients are
provided in the Supplementary Appendix, avail-
able with the full text of this letter at NEJM.org.)
We found that increased ST2 levels on day 14
after transplantation were significantly associ-
ated with an increased rate of nonrelapse death at
6 months in cohorts 2 and 3, findings that sup-
port the results of Vander Lugt et al. (cohort 1 was
a group of long-term survivors) (Table 1).
An unexpected finding was that an elevated
ST2 level was significantly associated with TA-TMA
in all three cohorts, a variable that was not re-
ported by Vander Lugt et al., and perhaps an
important cause of the excess mortality. We ad-
dressed the relationship between TA-TMA and
GVHD using multivariate linear regression in
data from recipients of allogeneic stem-cell trans-
plants. The association between the ST2 level
and GVHD was not significant in cohorts 1 and 3
(P=0.74 and P=0.56, respectively) but reached
statistical significance in cohort 2 (P=0.03). The
association between the ST2 level and TA-TMA
was strongly significant in cohorts 2 and 3
(P=0.003 and P=0.006, respectively) but not in
cohort 1 (P=0.28), probably because of selection
for survivors.
TA-TMA and GVHD commonly occur together,
and endothelial injury is common to both. Im-
mune suppression is used to treat GVHD but
will not improve TA-TMA. Untreated TA-TMA in
this weeks letters
1189 ST2 and Endothelial Injury as a Link between
GVHD and Microangiopathy
1190 Fish Oil in Pregnancy and Asthma in Offspring
1192 Genetic Risk, Lifestyle, and Coronary Artery
Disease
1195 Selumetinib in Plexiform Neurofibromas
1196 Geographic Variations in Controlled Trials

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 1. ST2 Levels on Day 14 after Transplantation in Three Cohorts of Patients.*

Condition Cohort 1 (N=95) Cohort 2 (N=110) Cohort 3 (N=107)

Median Values P Value Median Values P Value Median Values P Value

TA-TMA vs. no TA-TMA 96.6 ng/ml vs. 0.02 199.7 ng/ml vs. 0.03 81.3 ng/ml vs. <0.001
53.4 ng/ml 99.7 ng/ml 40.3 ng/ml
Acute GVHD vs. no acute 118.6 ng/ml vs. 0.29 112.2 ng/ml vs. 0.62 76.7 ng/ml vs. 0.007
GVHD 58.3 ng/ml 90.7 ng/ml 49.7 ng/ml
Nonrelapse death vs. no NA NA 263.4 ng/ml vs. 0.009 290.3 ng/ml vs. 0.001
nonrelapse death at 6 mo 104.9 ng/ml 50.7 ng/ml

* Cohort 1 includes patients who had survived for at least 1 year after hematopoietic stem-cell transplantation (HSCT). Cohort 2 includes con-
secutive patients who had undergone HSCT from November 2010 through May 2014 who were not included in cohort 1. Cohort 3 includes
consecutive patients who had undergone HSCT from June 2014 through October 2016 and who were not included in cohort 1. All the analy-
ses were performed with the use of enzyme-linked immunosorbent assay (plasma R&D Systems ELISA in cohorts 1 and 3 and serum
Critical Diagnostics ELISA in cohort 2). GVHD denotes graft-versus-host disease, NA not applicable, and TA-TMA transplant-associated
thrombotic microangiopathy.

patients with GVHD might be mistakenly classi-
fied as glucocorticoid-resistant GVHD, perhaps
leading to the reported association between the
condition and elevated ST2 levels. In our clinical
experience, specific treatment of both TA-TMA
and GVHD is needed for full resolution of symp-
toms when both disease processes are present.
We would propose that the careful evaluation of
transplant recipients with glucocorticoid-resis-
tant GVHD for signs of TA-TMA might identify
additional therapeutic options.
SethJ. Rotz, M.D.
ChristopherE. Dandoy, M.D.
StellaM. Davies, M.B., B.S., Ph.D.
Cincinnati Childrens Hospital Medical Center
Cincinnati, OH
stella.davies@cchmc.org
Disclosure forms provided by the authors are available with
the full text of this letter at NEJM.org.
1. Vander Lugt MT, Braun TM, Hanash S, et al. ST2 as a marker
for risk of therapy-resistant graft-versus-host disease and death.
N Engl J Med 2013;369:529-39.
2. Jodele S, Davies SM, Lane A, et al. Diagnostic and risk crite-
ria for HSCT-associated thrombotic microangiopathy: a study in
children and young adults. Blood 2014;124:645-53.
3. Dietrich S, Falk CS, Benner A, et al. Endothelial vulnerability
and endothelial damage are associated with risk of graft-versus-
host disease and response to steroid treatment. Biol Blood Mar-
row Transplant 2013;19:22-7.
4. Changsirikulchai S, Myerson D, Guthrie KA, McDonald GB,
Alpers CE, Hingorani SR. Renal thrombotic microangiopathy
after hematopoietic cell transplant: role of GVHD in pathogen-
esis. Clin J Am Soc Nephrol 2009;4:345-53.
5. Rachakonda SP, Penack O, Dietrich S, et al. Single-nucleo-
tide polymorphisms within the thrombomodulin gene (THBD)
predict mortality in patients with graft-versus-host disease. J
Clin Oncol 2014;32:3421-7.
DOI: 10.1056/NEJMc1700185

Fish Oil in Pregnancy and Asthma in Offspring

To the Editor: Bisgaard et al. (Dec. 29 issue)1
report a significant reduction of early childhood
asthma and wheeze after fish-oil supplementation
during the third trimester of pregnancy in women
without endocrine, heart, or kidney disorders.
A positive family history of asthma is an estab-
lished risk factor for the development of child-
hood asthma.2 Therefore, we would like to know
how many of the pregnant women in the two
study groups had a history of asthma or wheeze
or had active asthma or wheeze during their preg-
nancy, because a skewed distribution of asthma
or wheeze among study probands may have influ-
enced the study results. Also, how many women
gave fish-oil supplements to their children during
the postintervention surveillance period of 5 years,
especially since the study participants were made
aware of group assignment after 3 years?
Clemens Tempfer, M.D.
Ruhr University Bochum
Bochum, Germany
clemens.tempfer@rub.de

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