SARS-CoV-2–Induced Kawasaki-Like

Hyperinflammatory Syndrome: A Novel

COVID Phenotype in Children
Francesco Licciardi, MD,a,b Giulia Pruccoli, MD,a Marco Denina, MD,a,b Emilia Parodi, MD, PhD,a,b Manuela Taglietto, MD,b
Sergio Rosati, DVM,c Davide Montin, MD, PhDa,b

We describe 2 children with persistent fever and profuse diarrhea who abstract
developed signs of mucocutaneous involvement (conjunctivitis, fissured lips,
skin rash, erythema, and edema of the hands and feet). Blood tests revealed
elevated markers of inflammation, lymphopenia, thrombocytopenia, and a
Department of Pediatric and Public Health Sciences,
complement consumption. Afterward, diffuse edema with hypoalbuminemia University of Torino, Turin, Italy; cDepartment of Veterinary
appeared in the context of a capillary leak syndrome. In both patients, Sciences, University of Turin, Turin, Italy; and bRegina
Margherita Children’s Hospital, AOU Città della Salute e
repeated nasal swabs were negative for severe acute respiratory syndrome della Scienza di Torino, Turin, Italy
coronavirus 2 (SARS-CoV-2), but each patient had high titers of
Dr Licciardi gave substantial contribution to
immunoglobulin G and immunoglobulin M against the SARS-CoV-2 virus. The conception and design, drafted the article, and
negative PCR results in the presence of immunoglobulin M and reviewed and revised the manuscript; Drs Pruccoli
immunoglobulin G suggested that the inflammatory response developed in and Denina contributed to conception and design,
collected data, described the case reports, and
the late phase of viral infection, when SARS-CoV-2 was not detectable in the
reviewed and revised the manuscript; Drs Parodi
upper airway. In this report, we describe patients with what we propose to and Taglietto collected data, provided iconography,
name as SARS-CoV-2–induced Kawasaki-like hyperinflammatory syndrome. and revised the manuscript; Prof Rosati performed
SARS-CoV-2–induced Kawasaki-like hyperinflammatory syndrome seems to the serological test and interpretation of data and
reviewed the manuscript; Dr Montin supervised data
be caused by a delayed response to SARS-CoV-2. It resembles Kawasaki collection and critically reviewed and revised the
disease complicated by macrophage activation syndrome, although it has manuscript; and all authors approved the final
peculiar features, such as prodromal diarrhea, capillary leak syndrome, and manuscript as submitted and agree to be
accountable for all aspects of the work.
myocardial dysfunction. Intravenous corticosteroid treatment appears to be
DOI: https://doi.org/10.1542/peds.2020-1711
helpful.
Accepted for publication May 18, 2020
Address correspondence to Giulia Pruccoli, MD,
Regina Margherita Children’s Hospital, Piazza Polonia
On January 7, 2020, the Chinese Center followed by multiorgan failure. Since 94, 10126 Turin, Italy. E-mail: [email protected]
for Disease Control and Prevention the first reports, the development of PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online,
isolated a novel coronavirus, severe systemic inflammation has been 1098-4275).

acute respiratory syndrome proposed as a key factor related to poor Copyright © 2020 by the American Academy of
outcomes.1 Pediatrics
coronavirus 2 (SARS-CoV-2), from the
throat swab sample of a patient FINANCIAL DISCLOSURE: The authors have indicated
Preliminary data suggest that SARS- they have no financial relationships relevant to this
affected by interstitial pneumonia. CoV-2 infection in children is usually article to disclose.
Since then, SARS-CoV-2 cases have milder. In Italy, as of May 8, 2020, FUNDING: No external funding.
spread rapidly throughout China and 215 665 people were infected with POTENTIAL CONFLICT OF INTEREST: The authors have
worldwide, leading the World Health SARS-CoV-2, with ,2% being indicated they have no potential conflicts of interest
Organization to declare a pandemic ,18 years of age. Only three pediatric to disclose.
state on March 11, 2020. SARS-CoV-2 deaths have been reported.2 Systemic
initial symptoms are flulike, such as hyperinflammation due to SARS-CoV-2 To cite: Licciardi F, Pruccoli G, Denina M, et al.
rhinorrhea, fever, cough, fatigue, infection is currently considered rare in SARS-CoV-2–Induced Kawasaki-Like
myalgia, and, less frequently, diarrhea. children.3 The initial case patient Hyperinflammatory Syndrome: A Novel COVID
Phenotype in Children. Pediatrics. 2020;146(2):
In some patients, the infection can lead appears to have been a 6-month-old
e20201711
to severe interstitial pneumonia, girl with SARS-CoV-2 who presented

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PEDIATRICS Volume 146, number 2, August 2020:e20201711 CASE REPORT
with conjunctivitis, polymorphous
rash, swollen extremities, and
persistent fever. This patient was
treated as if she had Kawasaki disease
(KD) with intravenous
immunoglobulin and acetylsalicylic
acid and improved.4
In this report we describe two cases
of severe hyperinflammation with
similar clinical and laboratory
findings. Neither patient had
a positive nasal swab result, but both
had high immunoglobulin G (IgG) and
immunoglobulin M (IgM) titers
against SARS-CoV-2.

CASE REPORTS
Patient 1
On April 14, 2020, a 12-year-old boy
presented to our emergency
department with a 2-day history of
high fever and abdominal pain. His
previous medical history was
unremarkable. On admission, blood
tests revealed significant
lymphocytopenia (lymphocyte level
of 560 cells per mm3) and elevated
levels of inflammatory markers
(Fig 1). A nasopharyngeal swab was
negative for SARS-CoV-2. A chest
radiograph and echocardiogram were
normal, whereas an abdominal
ultrasound revealed mesenteric
lymphadenitis. Empirical antibiotics
FIGURE 1
were started, without clinical Time line of patients’ symptoms, laboratory findings, and therapy. Laboratory findings are expressed
improvement. During the following as a ratio of the normal value. Normal values were considered as follows: CRP, 10 mg/L; fibrinogen,
days, he developed mild 300 mg/dL; procalcitonin, 2 ng/mL; lymphocytes, 1500 cells per mm3; platelet count, 250 000/mm3;
conjunctivitis, erythema and cracked and ferritin, 150 ng/mL. IV, intravenous; IVIg, intravenous immunoglobulin.
lips, skin rash, erythema and edema
of the hands and feet, petechial cardiac involvement (reduced systolic with a 5-day history of fever, nausea
elements (Fig 2), persistent high function and pericardial effusion on and vomiting, diarrhea, and
fever, diarrhea (10–20 times daily), an echocardiogram, elevated troponin abdominal pain. He had a previous
and vomiting. He also developed mild T levels with normal creatine kinase diagnosis of periodic fever, aphthous
thrombocytopenia, complement myocardial band levels, and stomatitis, pharyngitis, and cervical
consumption, pleural effusion, weight electrocardiographic signs of adenitis. Both parents were health
gain, hypoalbuminemia with mild myocardial injury). He continued care workers. The mother had
proteinuria, and an increased ferritin intravenous corticosteroid for 2 anosmia and taste dysfunction for 1
level (580 ng/mL). Treatment with weeks, with subsequent month. A physical examination
methylprednisolone at 2 mg/kg was normalization of cardiac function. revealed bilateral conjunctivitis;
initiated, with immediate modest eyelid and scrotal erythema;
defervescence, prompt general Patient 2 skin rash on palms and soles, limbs,
improvement, and normalization of On April 18, 2020, a 7-year-old boy and back; petechial elements in the
blood tests. Meanwhile, he developed arrived in our emergency department lower limbs; dry lips; and de-

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2 LICCIARDI et al
FIGURE 2
Cutaneous manifestations on day 5 of illness. Patient 1: A, erythema and cracking of lips; B, mild conjunctivitis; C, erythema and edema of the hands; D,
petechial elements on feet. Patient 2: E, modest eyelid erythema; F, skin rash on palms; G, cutaneous erythema; H, petechial elements on feet.

epithelialized tongue (Fig 2). Blood on hospital day 3 (illness day 7) COVID19 [reported specificity
tests revealed lymphocytopenia, confirmed the cardiac injury (eg, 98.1%]; In3Diagnostic, Turin, Italy)
thrombocytopenia, low C3 and C4 abnormal troponin T levels, elevated found IgG and IgM antibodies
levels, hypoalbuminemia, and pro-brain natriuretic peptide levels, directed toward SARS-CoV-2 in both
significantly increased levels of and high levels of D-dimer, with patients.
ferritin (897 ng/mL) and other reduced systolic function on
inflammatory markers (Fig 1). A chest echocardiography). Treatment was
DISCUSSION
radiograph and electrocardiogram switched to intravenous
were normal, whereas an ultrasound immunoglobulin at 2 g/kg and These two cases reveal a novel severe
of the abdomen revealed the presence methylprednisolone at 2 mg/kg, and inflammatory syndrome that may
of enlarged mesenteric lymph nodes. we continued antibiotic therapy. The develop in children during the late
A nasopharyngeal swab specimen patient had progressive improvement phase of SARS-CoV-2 infection. SARS-
was negative for SARS-CoV-2. Broad- in clinical condition, laboratory, and CoV-2 acute infection may mimic KD
spectrum empirical antibiotics were imaging results. because it may present with
started. Subsequently, the patient persistent fever, rash, and
Because of the uncertainty about the
developed hypotension, tachycardia, conjunctivitis; our cases highlight that
cause of both of these cases, we
and tachypnea with oxygen SARS-CoV-2 infection may trigger
measured anti–S-specific IgG
desaturation. Noninvasive respiratory a severe inflammatory syndrome
antibodies to SARS-CoV-2 (LIAISON
even after seroconversion, when the
support was initiated, and he SARS-CoV-2 S1/S2 IgG [reported
virus might not be detected in upper
received a crystalloid solution, specificity 98.5%]; DiaSorin, Saluggia,
airways.5
followed by vasopressors. After fluid Italy) and found that both patients
resuscitation he developed right had moderate to high positive titers These two patients presented with
pleural effusion and cardiomegaly. of IgG antibodies versus SARS-CoV-2. diarrhea, abdominal pain, high fever,
Laboratory and instrumental tests A second confirmatory test (Eradikit elevated C-reactive protein (CRP) and

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PEDIATRICS Volume 146, number 2, August 2020 3
procalcitonin levels, and a low rapidly progressive capillary leak by fluid accumulation in body
lymphocyte count (phase1). Despite syndrome. cavities as a consequence of immune
appropriate broad-spectrum complex deposition and macrophage
Our patients did not have a PCR
antibiotic therapy, fever persisted, activation.13
positive for SARS-CoV-2, but they
and mucocutaneous involvement
had serological evidence of an Tavazzi et al14 demonstrated the
appeared: conjunctivitis, fissured
infection by using two different presence of viral SARS-CoV-2
lips, and acral rash. Both then
and highly specific tests. Although particles in a myocardial biopsy of
developed, in phase 2 of their illness,
little is known regarding the antibody a patient with severe myocarditis.
progressive thrombocytopenia, C3
kinetics, presence of IgM versus SARS-CoV-2 infection can be a trigger
and C4 consumption, hepatomegaly,
SARS-CoV-2 may be considered for cardiac injury, secondary to
capillary leak syndrome with
as a marker of a recent infection.8 a combination of direct vascular and
severely decreased albuminemia,
IgM cross-reactivity is improbable myocardial infection plus
diffuse edema, and, in one case,
because nasal swabs were negative proinflammatory stimulation, which
severe hypotension requiring
for other coronaviruses (229E, NL63, can occur at the same time or even
fluid resuscitation therapy.
OC43, and HKU1). post infection.15
Both patients improved after
intravenous corticosteroid therapy, The association between We emphasize that heart function
but they developed what appeared coronaviruses and KD was improved slowly; further follow-up
to be myocarditis in a third hypothesized in the past; in will be needed to determine if heart
phase. particular, Esper et al9 in 2005 found function will fully recover.
a PCR positive for New Haven
On initial presentation, we believed These two patients had mild
coronavirus in 8 of 11 infants with
they had a gastrointestinal bacterial respiratory symptoms. In fact, the
classic KD. Regarding SARS-CoV-2,
infection. In the second phase, both most significant manifestation was
recent reports suggest that it causes
patients fulfilled KD diagnostic diarrhea. We are now evaluating
capillary inflammation in the lungs
criteria. However, they had unusual whether SARS-CoV-2 is present in the
and skin, with complement activation
features, such as the age at disease stools, but the validity of such testing
through both alternative and lectin
onset and a low platelet count. This is unknown.
pathways.10 A direct viral infection of
last finding is not frequent among
the endothelial cells and diffuse
patients with KD, except when
endothelial inflammation can be
macrophage activation syndrome CONCLUSIONS
found in the kidneys, heart, and liver
(MAS) simultaneously develops. MAS
of patients affected by SARS-CoV-211. SARS-CoV-2 infection appears to have
is a rare life-threatening complication led to a late-phase serious
SARS-CoV-2 shares this capillary
of autoinflammatory and inflammatory syndrome in these two
tropism with other coronaviruses; in
autoimmune diseases6 that develops children. Although the clinical
particular, severe acute respiratory
in 1.1% to 1.9% of patients with KD. presentation bears some similarities
syndrome coronavirus 1 causes
In 2015 Wang et al7 published to KD-MAS, unusual features, such as
complement activation in mouse
a report of 8 patients with
lungs, and C32/2 mice have capillary leak, were present. We
macrophage activation syndrome in propose that this clinical phenotype
considerably less respiratory
Kawasaki disease (MAS-KD). All
dysfunction than wild-type mice.12 be named SCiKH syndrome (or SARS-
patients had serum ferritin levels CoV-2–induced Kawasaki-like
These data suggest that the
.684 ng/mL and aspartate hyperinflammatory syndrome).
mucocutaneous involvement, as
aminotransferase levels .100 U/L,
well as the decrease of C3, C4,
87.5% had a platelet count of
and platelet counts, may be
,100 000/mm3. Coronary ACKNOWLEDGMENTS
a consequence of
involvement occurred in 25% of
a microvasculopathy that leads to We thank Prof Rossana Cavallo and
patients.
capillary leakage. The clinical picture Drs Maria Avolio and Barbara Colitti
MAS-KD has many similarities described in our report has many for performing serological tests; Drs
with the clinical picture of our analogies with a well-known hyper Marisa Zoppo, Federica Mignone,
patients, although these two inflammatory syndrome caused Silvia Garazzino, and Carlo Scolfaro
patients had unique features in cats by feline coronavirus: for clinical management of patients;
(Supplemental Table 1), such feline infectious peritonitis. Monica Mantovani for English
as the absence of coronary Feline infectious peritonitis is language revision; Cecilia Pruccoli for
involvement, the development a fatal immune-mediated disease; providing graphic support; and all the
of myocardial dysfunction, and its effusive form is characterized ICU and emergency department

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4 LICCIARDI et al
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PEDIATRICS Volume 146, number 2, August 2020 5
 SARS-CoV-2−Induced Kawasaki-Like Hyperinflammatory Syndrome: A Novel
COVID Phenotype in Children
Francesco Licciardi, Giulia Pruccoli, Marco Denina, Emilia Parodi, Manuela
Taglietto, Sergio Rosati and Davide Montin
Pediatrics originally published online May 21, 2020; originally published online May
21, 2020;

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020-1711#BIBL
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 SARS-CoV-2−Induced Kawasaki-Like Hyperinflammatory Syndrome: A Novel
COVID Phenotype in Children
Francesco Licciardi, Giulia Pruccoli, Marco Denina, Emilia Parodi, Manuela
Taglietto, Sergio Rosati and Davide Montin
Pediatrics originally published online May 21, 2020; originally published online May
21, 2020;

The online version of this article, along with updated information and services, is
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http://pediatrics.aappublications.org/content/early/2020/07/24/peds.2020-1711

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