Editorials
5. Ikematsu H, Hayden FG, Kawaguchi K, et al. Baloxavir mar-
boxil for prophylaxis against influenza in household contacts.
N Engl J Med 2020;​383:​309-20.
6. Stewart RJ, Flannery B, Chung JR, et al. Influenza antiviral
prescribing for outpatients with an acute respiratory illness and
at high risk for influenza-associated complications during 5 in-
fluenza seasons — United States, 2011-2016. Clin Infect Dis
2018;​66:​1035-41.
7. Hirotsu N, Sakaguchi H, Sato C, et al. Baloxavir marboxil in
Japanese pediatric patients with influenza: safety and clinical
and virologic outcomes. Clin Infect Dis 2019 September 20
(Epub ahead of print).
8. Takashita E, Ichikawa M, Morita H, et al. Human-to-human
Growth and the Microbiome — Integrating
Global Health with Basic Science
Ramnik J. Xavier, M.D.
Linear growth failure, or stunting, is a prevalent
condition arising from undernutrition that has
been identified as a major global health prob-
lem.1 Stunting is strongly associated with eco-
nomic, health, and neurocognitive sequelae,
making linear growth a major nutrition priority.
Interventions that have focused on the supple-
mentation of macronutrients and micronutrients2,3
and targeted efforts to improve water quality,
sanitation, and hygiene have shown limited ef-
ficacy in combating growth failure.4
One potential causative factor that numerous
studies have associated with stunting is environ-
mental enteropathy (also called environmental
enteric dysfunction [EED]), a subclinical syn-
drome that was first described in the 1960s.
This disorder, which has been observed in per-
sons residing in and traveling to tropical loca-
tions, is characterized by intestinal villous blunt-
ing and histologic changes that are consistent
with intestinal inflammation. Efforts to disen-
tangle and decipher the relationship between
stunting and EED have raised a series of critical
questions. Does such enteropathy, as currently
defined, lead to stunted growth? Do microbes
that are resident in the small intestine contribute
to the pathogenesis of enteropathy? What are the
molecular mechanisms connecting enteropathy
to stunted growth?
A study by Chen and colleagues5 in this issue
of the Journal presents evidence that the hitherto
unexplored duodenal microbiota can induce vil-
n engl j med 383;4  nejm.org  July 23, 2020
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Copyright © 2020 Massachusetts Medical Society. All rights reserved.
transmission of influenza A(H3N2) virus with reduced suscepti-
bility to baloxavir, Japan, February 2019. Emerg Infect Dis 2019;​
25:​2108-11.
9. Hayden FG, Belshe R, Villanueva C, et al. Management of
influenza in households: a prospective, randomized comparison
of oseltamivir treatment with or without postexposure prophy-
laxis. J Infect Dis 2004;​189:​440-9.
10. Hayden FG, Gubareva LV, Monto AS, et al. Inhaled zanamivir
for the prevention of influenza in families. N Engl J Med 2000;​
343:​1282-9.
DOI: 10.1056/NEJMe2022702
Copyright © 2020 Massachusetts Medical Society.
lous flattening that is associated with childhood
stunting, particularly in children who do not have
a response to nutritional therapy. This landmark
investigation is built on a decade of research
probing causal roles of the intestinal microbiota
in nutritional phenotypes. Matching the scale of
the problem, the methodical process by which
this study has been constructed over time is in
itself instructive. By connecting clinical field
sites to state-of-the-art bench experimentation,
the authors provide a molecular definition of
EED that in turn yields potential mechanisms
and therapeutic targets for the vexing problem
of stunting.
Knowledge from mouse models supports a
critical role in postnatal development for the
gastrointestinal microbiome, where it has a ma-
jor effect on the maintenance of gut-barrier
function, on the innate and adaptive immune
systems, and on shaping host metabolism and
nutrient processing. To this end, Chen et al.,
along with members of the International Centre
for Diarrhoeal Disease Research, Bangladesh, and
other collaborators, sought to describe the tra-
jectory of microbial communities in human
populations from distinct backgrounds. In lon-
gitudinal studies involving unrelated children
with varying nutritional statuses who were
raised in Malawi, Bangladesh, and other sites,
the authors have identified shared components
of the microbiome,6,7 including postnatal devel-
opment features among children across geogra-
391
 The n e w e ng l a n d j o u r na l
phies and cultures and altered development of
microbiota in undernourished and stunted chil-
dren as compared with healthy controls, and
have confirmed the challenges of using nutri-
tional therapy to treat stunting.8 Why the re-
sponse to nutritional intervention is impaired in
some stunted children and whether this impair-
ment is influenced by the gut microbiome are
questions that have remained unanswered.
The present study focuses on slum-dwelling
Bangladeshi children of approximately 18 months
of age with stunting that persisted despite re-
ceiving a primarily nutrition-focused intervention
composed of egg, cow’s milk, micronutrients,
and anthelmintic drugs. Endoscopic duodenal
biopsies were performed in these children to
investigate the presence of EED. Intriguingly,
histopathological scoring had no correlation
with length-for-age z scores, a standardized
measure of linear growth. Moreover, no signifi-
cant association was observed among composite
scores of fecal and plasma biomarkers, such as
stool alpha-1 antitrypsin, used in clinical studies
to characterize EED. These observations prompted
the hypothesis that scoring systems can obscure
the sequence of events leading to the develop-
ment of disease.
Thus, the investigators pursued a new mecha-
nistic definition of enteropathy by integrating
the duodenal microbiome, assessing microbes at
the site of disease location, and using paired
sampling of plasma and duodenal proteomes to
develop a predictive signature of linear growth.
They found that there was a significant negative
correlation between the length-for-age z score
and the total bacterial load and absolute levels of
14 taxa in the duodenal microbiome. Further-
more, the investigators identified protein groups
in which levels covaried with the absolute levels
of these 14 taxa, thus yielding insights into po-
tential mechanisms by which duodenal microbes
alter human biology. One protein that was sig-
nificantly associated with the duodenal micro-
bial load was regenerating family member 3 alpha
(REG3A), which strongly correlated with the lipo­
calin-2 level in the duodenal proteome. Insulin-
like growth factor 1 (IGF-1) and other IGF-
binding proteins were also implicated in the
plasma analysis, and IGF-1 interactions with
plasma proteome profiles detected osteoproteg­
erin, a decoy receptor for RANK ligand. These
392 n engl j med 383;4  nejm.org  July 23, 2020
The New England Journal of Medicine
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Copyright © 2020 Massachusetts Medical Society. All rights reserved.
of m e dic i n e
associations suggest that IGF-1 axis impairment
is one mechanism underlying linear growth
stunting in this population.
Using the associations found in humans, the
investigators evaluated the mechanism underly-
ing villous flattening and stunting in gnotobi-
otic mice. They found that cultured strains from
duodenal aspirates obtained from children with
EED transmitted features of increased crypt
length, disruption of the small-intestine barrier,
and bacterial translocation when introduced into
5-week-old mice. Previous studies have shown
that microbial consortia from the gut microbiome
of children with kwashiorkor also transmit to
mice an environmental enteropathy phenotype.9
A complementary line of inquiry showed that
consumption of a moderately malnourished diet,
in combination with iterative oral exposure to
commensal Bacteroidales species and Escherichia
coli, induces an environmental enteropathy pheno-
type in the mouse.10 These collective data pro-
vide clues as to how duodenal-residing microbes
contribute to enteropathy. What remains unclear
is whether these mouse models sufficiently rep-
licate the features of stunted growth to com-
pletely clarify the relationship with enteropa-
thy. Another challenge is the ethical inability to
perform endoscopy in healthy children, which
prevents the use of a control population of pedi-
atric microbes in the mouse experiments.
The study of the duodenal microbiome and
undernutrition by Chen and colleagues reclas-
sifies our understanding of gut physiology in
children with stunted growth. The authors iden-
tify the duodenal microbiome as a plausible causal
factor underlying stunting and pinpoints specific
strains capable of transmitting enteropathy in a
mouse model. Moreover, their proteomic analy-
sis identified a swath of potential biomarkers
and mechanistic drivers of stunted growth. This
work is reminiscent of the identification of Heli-
cobacter pylori as a cause of ulcers by mechanisti-
cally linking a disease that occurs within an
anatomical location to the bacteria residing there.
Observations from this study raise several addi-
tional questions. Do the duodenal microbiota
harbor previously unrecognized bad actors? Is
environmental enteropathy a form of bacterial
overgrowth in the small intestine? Can we address
the underlying disease by redesigning interven-
tions regarding nutritional efforts that modulate
 Editorials

the microbiome? This inspiring study brings
into focus a panoramic view of human health
and disease and underscores the importance of
global collaboration in striving for innovation
and mechanism-based interventions to address
the enigmatic problem of stunted growth.
Disclosure forms provided by the author are available with the
full text of this editorial at NEJM.org.
From Massachusetts General Hospital and Harvard Medical
School, Boston, and Broad Institute, Cambridge — both in
Massachusetts.
1. Black RE, Victora CG, Walker SP, et al. Maternal and child
undernutrition and overweight in low-income and middle-income
countries. Lancet 2013;​382:​427-51.
2. Prentice AM, Ward KA, Goldberg GR, et al. Critical windows
for nutritional interventions against stunting. Am J Clin Nutr
2013;​97:​911-8.
3. Lauer JM, McDonald CM, Kisenge R, et al. Markers of sys-
temic inflammation and environmental enteric dysfunction are
not reduced by zinc or multivitamins in Tanzanian infants: a ran-
domized, placebo-controlled trial. J Pediatr 2019;​210:​34-40.e1.
4. Luby SP, Rahman M, Arnold BF, et al. Effects of water qual-
ity, sanitation, handwashing, and nutritional interventions on
diarrhoea and child growth in rural Bangladesh: a cluster ran-
domised controlled trial. Lancet Glob Health 2018;​6(3):​e302-e315.
5. Chen RY, Kung VL, Das S, et al. Duodenal microbiota in
stunted undernourished children with enteropathy. N Engl J Med
2020;​383:​321-33.
6. Yatsunenko T, Rey FE, Manary MJ, et al. Human gut micro-
biome viewed across age and geography. Nature 2012;​486:​222-7.
7. Subramanian S, Huq S, Yatsunenko T, et al. Persistent gut
microbiota immaturity in malnourished Bangladeshi children.
Nature 2014;​510:​417-21.
8. Gehrig JL, Venkatesh S, Chang H-W, et al. Effects of micro-
biota-directed foods in gnotobiotic animals and undernourished
children. Science 2019;​365:​eaau4732.
9. Kau AL, Planer JD, Liu J, et al. Functional characterization of
IgA-targeted bacterial taxa from undernourished Malawian chil-
dren that produce diet-dependent enteropathy. Sci Transl Med
2015;​7(276):​276ra24.
10. Brown EM, Wlodarska M, Willing BP, et al. Diet and specific
microbial exposure trigger features of environmental enteropa-
thy in a novel murine model. Nat Commun 2015;​6:​7806.
DOI: 10.1056/NEJMe2017496
Copyright © 2020 Massachusetts Medical Society.

Childhood Multisystem Inflammatory Syndrome

— A New Challenge in the Pandemic
Michael Levin, F.Med.Sci., Ph.D.

The recognition and description of new diseases
often resemble the parable of the blind men and
the elephant, with each declaring that the part
of the beast they have touched fully defines it.
As the coronavirus disease 2019 (Covid-19) pan-
demic has evolved, case reports have appeared
describing children with unusual febrile illness-
es that have features of Kawasaki’s disease,1
toxic shock syndrome,2 acute abdominal condi-
tions, and encephalopathy, along with other re-
ports of children with fever, elevated inflamma-
tory markers, and multisystem involvement.3-5 It
is now apparent that these reports were describ-
ing different clinical presentations of a new child-
hood inflammatory disorder.
A case definition for the emerging disorder
was published in late April 2020,5 after U.K. pedia-
tricians alerted the National Health Service to an
unusual inflammatory illness, termed “pediatric
inflammatory multisystem syndrome temporally
associated with severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2),” or PIMS-TS.6 Simi-
lar cases were rapidly reported from many other
countries.3,4 The U.S. Centers for Disease Control
and Prevention (CDC) and the World Health Or-
ganization (WHO) subsequently published their
own differing definitions of the disorder, which
they named multisystem inflammatory syndrome
in children (MIS-C).
Two reports now appearing in the Journal de-
scribe the epidemiology and clinical features of
the new disorder in the United States. Dufort
and colleagues describe the results of active
mandatory surveillance for MIS-C in 106 hospi-
tals in New York State, with 191 cases reported
to the state health department as of May 10,
2020, of which 99 met the case definition.7 Feld-
stein and colleagues report 186 cases identified
by targeted surveillance in 26 U.S. states over a
2-month period.8 Together with the reports from
other countries,1-6 these studies describe the
new childhood inflammatory disorder that has
emerged during the Covid-19 pandemic.
With approximately 1000 cases of MIS-C (in-
cluding, here and below, those that have been
classified as PIMS-TS) reported worldwide, do

n engl j med 383;4  nejm.org  July 23, 2020 393

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