COVID-19 immunology, MIS-C, and allergic diseases

COVID-19: Immunology,
MIS-C and allergic disease
Topic Review
June 19th, 2020
Rapisa Nantanee, M.D.
Pediatric Allergy and Immunology Unit
King Chulalongkorn Memorial Hospital

Outline
COVID-19
Multisystem inflammatory
disorder in children (MIS-
C)
COVID-19 in allergic,
autoimmune/inflammatory
patients

Outline: COVID-19
• The Virus
• Naming the disease
• Current Situation
• Immunology of COVID-19
• Signs and symptoms of COVID-19
• Diagnostics tests
• Treatment

Introduction: The Virus
• Coronaviruses (CoVs) are large enveloped viruses with a single-
stranded, nonsegmented, positive sense RNA genome that spans
approximately 30 kilobases, making it the largest known genome of any
RNA virus.
• The family of Coronaviridae is divided into two subfamilies: Coronavirinae and
Torovirinae.
• Coronavirinae include the genera
• Alpha-, Betacoronaviruses, infecting only mammals
• Gamma-, and Deltacoronaviruses which infect both mammals and birds
• All novel CoVs (including SARS-CoV2) are betacoronaviruses.
• Seven CoVs are recognized as human pathogens.
S. Felsenstein, et al. Clinical Immunology 215 (2020) 108448. Published: 27 April 2020.

Introduction: The Virus
• Three highly pathogenic, novel zoonotic CoVs have emerged during the
last 18 years.
• The SARS coronavirus (SARS-CoV), now named SARS-CoV-1,was discovered in
November 2002.
• The Middle East respiratory syndrome coronavirus (MERS-CoV) in June 2012
• SARS-CoV-2 was identified in December 2019 after sequencing clinical samples from
a cluster of patients with pneumonia in Wuhan, China.
• MERS-CoV, SARS-CoV and SARS-CoV2 have a natural reservoir in
bats.
• Infection of humans likely occurred through intermediate hosts, including dromedary
camels (MERS), the masked palm civet (SARS) and the pangolin (SARS-CoV2).
AK. Azkur, et al. doi:10.1111/all.14364. Published: 12 May 2020.

Structure of severe acute
respiratory syndrome
coronavirus 2 (SARS-CoV2)
• Coronaviruses are spherical in shape.
• Their most prominent feature are club-
like projections on the virus surface
which are referred to as “spikes”.
• The virus membrane contains 4
structural components:
• The spike (S) protein is the primary
determinant for host tropism and
pathogenicity, and the main target for
neutralizing antibodies and therefore of
great interest in terms of immunological
response and vaccine design.
• The envelope (E) protein
• The membrane (M) protein
• The nucelocapsid (N) protein

The Virus
• Three central variants of the current virus that differ in their
amino acid sequence have been identified, namely A, B, and C.
• The ancestral type A and the mutated type C are found in significant
proportions outside East Asia, mainly in Europe and in the United
States.
• The B type which has mutated and spread is the most common type in
East Asia.
AK, Azkur, et al. doi:10.1111/all.14364. Published: 12 May 2020.

Naming the disease
• The disease caused by SARS-CoV-2 is named coronavirus
disease-2019 (COVID-19).
• Since its first report in December 2019 in Wuhan, China,
COVID-19 was declared a pandemic by the World Health
Organization (WHO) on March 11th, 2020 and continued to
aggressively spread across the globe infecting more than 3
million confirmed cases.

Current Situation
WHO. https://covid19.who.int/
13 June 2020.

Current Situation: South-East Asia
13 June 2020.

Current Situation: Thailand
13 June 2020.

Epithelial infection and viral cycle
• SARS-CoV-2 recognizes angiotensin-
converting enzyme 2 (ACE2) to attach
to cells, particularly respiratory
epithelial cells of the host.
• This process is dependent on the host
serine protease TMPRSS2, which
cleaves viral spike protein at the S1/S2.
• S2 subunit allows for fusion of viral and
cellular membranes.
• Following receptor binding, the virus
can enter the cell cytoplasm via
endocytosis.

Virus binding,
internalization
to epithelial
cells and
replication

MZ. Tay, et al. Nat Rev Immunol 20, 363–374 (2020). Published: 28 Apr 2020.

Immune evasion strategies of SARS-CoV2
• While RNA viruses usually activate TLR3 and/or 7
in endosomes (b) and cytosolic RNA sensors
RIG-I and MDA-5 (c)
• SARS-COV2 effectively suppresses the activation
of TNF receptor-associated factors (TRAF) 3 and
6, thereby limiting activation of the transcription
factors NFκB and IRF3 and 7, thereby
suppressing early pro-inflammatory responses
through type I interferons (IFN) and pro-
inflammatory effector cytokines IL-1, IL-6 and
TNF-α (red symbols).
• Furthermore, novel CoVs inhibit the activation of
STAT transcription factors (d) in response to type I
IFN receptor activation, which further limits
antiviral response mechanisms.
• Altogether, this prohibits virus containment
through activation of anti-viral programs and
the recruitment of immune cells.
SARS-CoV2 infects airway epithelial cells through
interactions with the trans-membrane enzyme ACE2

Inflammatory response through monocytes
macrophages
• Uninfected monocytes/macrophages
from the blood stream invade the lungs
where they detect virus particles and/or
cytoplasmic and nuclear components.
• Within immune complexes, these particles
are taken up into the cell (a) where they
are presented to TLRs, activating NFκB
and/or IRF dependent pro-inflammatory
pathways (b,c).
• As a result, uninfected
monocytes/macrophages produce
significant amounts of pro-inflammatory
cytokines (d,e) which recruit additional
innate and adaptive immune cells and
cause additional tissue damage.
Uninfected monocytes/macrophages

Immune evasion strategies of SARS-CoV2
• However, immune complexes consisting of
ineffective antibodies against e.g. seasonal
CoVs and virus particles may be taken up by
macrophages through Fcγ receptors resulting in
their infection (b).
• In a process referred to as antibody directed
enhancement (ADE), virions inhibit type I IFN
signaling in infected macrophages while
allowing pro-inflammatory IL-1, IL-6 and TNF-
α expression, which may contribute to
hyperinflammation and cytokine storm
syndrome (c,d).
• Inhibited type 1 IFN signaling suppresses anti-
viral programs, while increased IL-1, IL-6 and
TNF-α expression auto-amplifies itself through
positive feedback loops (f).
Tissue monocytes/macrophages express ACE2 to a significantly
lower extent, making infection through this route less likely.

Inflammatory mechanisms in immune
complex vasculitis

N. Vabret, et al. Immunity (2020), https://doi.org/10.1016/j.immuni.2020.05.002. Published: 6 May 2020.
Severe
Disease
Neutrophil-to-
lymphocyte
ratio
Serum amyloid
protein

Severe
Disease

ACE2 Expression in Organs and Systems Most
Frequently Implicated in COVID-19 Complications
• Lymphopenia, increases in
proinflammatory markers and cytokines,
and potential blood hypercoagulability
characterize severe COVID-19 cases with
features reminiscent of cytokine release
syndromes.
• After SARS-CoV-2 binds to ACE2
overexpressing organs, such as the
gastrointestinal tracts and kidneys, increases
in non-specific inflammation markers are
observed.
• In more severe cases, a marked systemic
release of inflammatory mediators and
cytokines occurs, with corresponding
worsening of lymphopenia and potential
atrophy of lymphoid organs, impairing
lymphocyte turnover

Host factors affecting individual risk
and outcomes
• Poor outcomes are associated with age
• Antibody titres wane over time, most obvious in those over 60 years.
• Antibody-bound virions can enter susceptible cells, such as macrophages
through Fcγ receptor ligation in a process termed antibody- dependent
enhancement (ADE).
• In other viral infections (e.g. Dengue fever), ADE allows immune cell infection and
reduces type I IFN dependent antiviral responses while promoting pro-inflammatory
IL-6 and TNF-α expression.
• Massive recall antibody production in individuals with a history of exposure to
seasonal coronaviruses but waning titres, such as the elderly, can result in
immune complex deposition and promote inflammation and damage,
including immune complex vasculitis.

Host factors affecting individual risk
and outcomes
• Poor outcomes are associated with age (cont.)
• Live vaccinations (e.g. measles or BCG)
• Vaccines protect beyond their target antigen through induction of innate immune
mechanisms termed non-specific heterologous effects.
• Limited memory T cell repertoires are a feature of immune
senescence and associated with disease progression and T cell
mediated damage in other viral infections, such as virus hepatitis and
infective mononucleosis

Hypothetical mechanism by SARS-CoV-2 in establishing an
inflammatory feedback loop between IL-6 and angiotensin II
M. Catanzaro, et al. Signal Transduction and Targeted Therapy (2020) 5:84. Published: 29 May 2020.

S. Bunyavanich, et al. doi:10.1001/jama.2020.8707. Published: 20 May 2020.
• Nasal epithelium was collected
using a cytology brush. RNA was
isolated within 6 months. RNA
samples were checked for
quality and sequenced as a
single batch in 2018
• ACE2 gene expression was
significantly higher in older
children (P = .01), young adults
(P < .001), and adults (P = .001).

ACE2 expression is decreased in the nasal epithelium of
children with allergic sensitization (Sens) and allergic asthma
DJ. Jackson, et al. https://doi.org/10.1016/j.jaci.2020.04.009. Published: 22 Apr 2020.
• In 3 cohorts of children and
adults, total RNA was extracted
from nasal or lower airway
epithelial brush samples, with
RNA sequencing performed.
• Allergic sensitization was
inversely related to ACE2
expression in the nasal
epithelium regardless of asthma
status.
• Lower levels of ACE2 according
to the degree of IgE
sensitization among children
with asthma

Clinical disease presentations of COVID-19
Ashley L. St. John and Abhay P. S. Rathore. www.jimmunol.org/cgi/doi/10.4049/jimmunol.2000526
Published: 8 June 2020.

The iceberg
of the
COVID-19
pandemic
M. Akdis, et al. doi:10.1111/all.14364. Published: 12 May 2020.

Symptoms
• The most common symptoms of COVID-19 are fever, fatigue,
and respiratory symptoms, including cough, sore throat and
shortness of breath.
• The majority of COVID-19 cases (about 80%) is asymptomatic
or exhibits mild to moderate symptoms, but approximately the
15% progresses to severe pneumonia and about 5% eventually
develops acute respiratory distress syndrome (ARDS), septic
shock and/or multiple organ failure.

Specific antibody response to SARS-CoV-2
M. Akdis, et al. doi:10.1111/all.14364. Published: 12 May 2020.

Antibody-Mediated Immunity in SARS-CoV-2

Diagnostic tests
N. Sethuraman, et al. JAMA. 2020;323(22):2249–2251. Published: 6 May 2020.

JM. Sanders, et al. JAMA. 2020;323(18):1824-1836. Published: 13 Apr 2020.

Schematic representation of SARS-CoV-2-driven
signaling pathways and potential drug targets

Multisystem inflammatory
disorder in children (MIS-C)

Multisystem Inflammatory Syndrome
in Children
• Multisystem Inflammatory Syndrome in Children (MIS-C, also referred
to as pediatric multisystem inflammatory syndrome–temporally
associated with SARS-CoV-2 [PMIS-TS])
• Previously healthy children with severe inflammation and Kawasaki
disease-like features were identified to have current or recent infection
with SARS-CoV-2.
• Emerging data suggest that MIS-C may be associated with pediatric
patients who are slightly older than children typically seen with Kawasaki
disease, and some cases of MIS-C in young adults have been reported.
• Epidemiologic and clinical data suggest that MIS-C may represent a post-
infectious inflammatory phenomenon rather than a direct viral process.
COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines.
National Institutes of Health. Last update 11 June 2020.

SARS-CoV-2-related paediatric inflammatory
multisystem syndrome, an epidemiological
study, France, 1 March to 17 May 2020
A. Belot, et al. Euro Surveill. 2020;25(22). Published: 4 June 2020.

E. Whittaker, et al. JAMA. doi:10.1001/jama.2020.10369. Published: 8 June 2020.
• Children and adolescents
• Fever
• Multisystem organ
involvement
• Elevated markers of
inflammation
• +/- Evidence of COVID-19

• Children and adolescents 0–19 years of age with fever ≥ 3
days
• AND two of the following:
• a) Rash or bilateral non-purulent conjunctivitis or muco-cutaneous
inflammation signs (oral, hands or feet).
• b) Hypotension or shock.
• c) Features of myocardial dysfunction, pericarditis, valvulitis, or
coronary abnormalities (including ECHO findings or elevated
Troponin/NT-proBNP),
• d) Evidence of coagulopathy (by PT, PTT, elevated d-Dimers).
• e) Acute gastrointestinal problems (diarrhoea, vomiting, or abdominal
pain).
• AND
• Elevated markers of inflammation such as ESR, C-reactive protein, or
procalcitonin.
• AND
• No other obvious microbial cause of inflammation, including bacterial
sepsis, staphylococcal or streptococcal shock syndromes.
• AND
• Evidence of COVID-19 (RT-PCR, antigen test or serology positive), or
likely contact with patients with COVID-19.
Multisystem inflammatory disorder in
children and adolescents
Kawasaki disease
• Classic KD is diagnosed in the presence of fever
for at least 5 d together with at least 4 of the 5
following principal clinical features:
• 1. Erythema and cracking of lips, strawberry
tongue, and/or erythema of oral and
pharyngeal mucosa
• 2. Bilateral bulbar conjunctival injection
without exudate
• 3. Rash: maculopapular, diffuse
erythroderma, or erythema multiforme-like
• 4. Erythema and edema of the hands and
feet in acute phase and/or periungual
desquamation in subacute phase
• 5. Cervical lymphadenopathy (≥1.5 cm
diameter), usually unilateral
WHO. Scientific brief. 15 May 2020.
BW. McCrindle, et al. Circulation. 2017;135:e927–e999.

Clinical Characteristics of 58 Children With a
Pediatric Inflammatory Multisystem Syndrome
Temporally Associated With SARS-CoV-2
• Pediatric inflammatory multisystem syndrome temporally
associated with severe acute respiratory syndrome coronavirus
2 (SARS-CoV-2) (PIMS-TS)
• In this study, children were included who met the UK, CDC, or
WHO definitions for PIMS-TS, without requiring proof of
SARS-CoV-2 exposure, and investigated the value of this
requirement in our analysis.

E. Whittaker, et al. JAMA.
doi:10.1001/jama.2020.1036
9. Published: 8 June 2020.
• Clinical patterns
• (1) a group with shock (inotrope use or
fluid resuscitation >20 mL/kg) (n = 29)
• (2) a group that met criteria for KD (n =
13)
• (3) a group with fever and inflammation
who did not have shock or did not meet
the clinical criteria for KD (n = 23)

Comparison of Laboratory Findings in Patients
With Shock and Coronary Artery Aneurysms
• Children with PIMS-TS who developed shock (n = 29) had
numerically higher CRP and neutrophil counts, lower albumin, lower
lymphocyte counts, and elevated troponin and NT-proBNP
concentrations compared with those without shock.
• Eight children had abnormally dilated coronary arteries (z score
>2).
• Giant coronary artery aneurysms (z score >10) were documented in 2
patients.
• Laboratory findings among children who developed coronary artery dilatation
or aneurysms were not meaningfully different from those without coronary
artery aneurysms.

Comparison of Age in 4 Different Patient Groups
The comparison groups of
children from cohorts with
other inflammatory diseases
included
• 1132 patients with KD
(mean age, 2.7 years
[IQR, 1.4-4.7])
• 45 with KD shock
syndrome (mean age,
3.8 years [IQR, 0.2-18])
• 37 with toxic shock
syndrome (mean age,
7.4 years [IQR, 2.4-15.4])
Patients with PIMS-TS
were generally older
than those with KD or KD
shock syndrome and had
• Higher white blood
cell count
• Neutrophil count
• CRP
• More profound
lymphopenia and
anemia
• Lower platelet counts
• Higher fibrinogen
levels
• Greater elevation of
troponin

Multisystem Inflammatory Syndrome
in Children
• Currently, there is limited information available about risk factors,
pathogenesis, clinical course, and treatment for MIS-C.
• Supportive care remains the mainstay of therapy.
• There are currently insufficient data for the COVID-19 Treatment
Guidelines Panel to recommend either for or against any therapeutic
strategy for the management of MIS-C.
• Many centers consider the use of intravenous immune globulin, steroids,
and other immunomodulators (including interleukin-1 and interleukin-6
inhibitors) for therapy, and antiplatelet and anticoagulant therapy.
• The role of antiviral medications that specifically target SARS-CoV-2 is not
clear at this time.
COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines.
National Institutes of Health. Last update 11 June 2020.

COVID-19 in allergic,
autoimmune/inflammatory
patients

Acute At Home Management of Anaphylaxis
During the Covid-19 Pandemic
TB. Casale, et al. J Allergy Clin Immunol Pract 2020;8:1795-7. Published: 18 Apr 2020.

COVID-19 in patients receiving
immune modulating treatment
• Immune modulation or suppression was not identified as a
risk factor for poor prognosis in China or Italy.
• Immune suppression and associated altered immune function
may predispose patients to infection and potentially prolong
virus spreading.
• Patients receiving immune modulating treatment may be prone
to secondary infections, such as bacterial pneumonia.

• Some immune modulating drugs may protect from viral
infections.
• Antimalarial drugs (chloroquine, hydroxychloroquine) may inhibit
tissue infection and viral replication.
• Immune modulating medications (anti-malarial drugs, classical as
well as biologic DMARDs, and others) may prevent or control cytokine
storm syndromes.

• Uncontrolled discontinuation of immune modulating treatment may
result in disease flares in autoimmune/inflammatory conditions,
organ rejection in transplant patients, or reoccurrence of
malignancies, which (on top of obvious effects) may also all increase
the risk for viral infection.
• National and international societies, including the ACR and EULAR,
recommend continuation of treatment in the absence of
symptoms and alterations to existing treatment regimens only in
agreement with and under close monitoring by the responsible
clinical service.

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