Kawasaki disease epidemic: the dilemma of evaluating clinical
models
Romina Gallizzi 1, Giovanni Battista
Pajno 1.
1 Department of Human Pathology of Adulthood and
Childhood Gaetano Barresi, Gaetano Martino University Hospital,
University of Messina, Messina, Italy
*Corresponding Author
Romina Gallizzi
Department of Human Pathology of Adulthood and Childhood Gaetano
Barresi, University of Messina, Messina, Italy
Gaetano Martino University Hospital, UOC Pediatria
Via Consolare Valeria
Messina, 98125, Italy
Tel: 090 221 3154
Fax: 090 221 3170
E-mail: rgallizzi@unime.it
To the Editor,
Following the outbreak of the coronavirus 2019 disease (Covid-19)
pandemic, some authors have highlighted a link between severe forms of
Covid-19 disease and the so-called cytokine storm, with increased levels
of ferritin (1), characterized by an abnormal activation of the
patient’s immune system with the release of numerous inflammation
mediators such as IL-1, IL-6, TNF and numerous chemokines.
This scenario is very heterogeneous. Some patients with Sars-Cov-2
infection develop secondary lymphohistiocytic hemophagocytosis (sHLH),
while others, do not meet the criteria of sHLH but show some
characteristics similar to hyperferritinemic syndrome (2).
In the pediatric field, a new multisystem inflammatory disease similar
to Toxin Shock Syndrome (TSS) and atypical Kawasaki disease (KD) with
exposure or suspected or proven SARS-CoV 2 infection has been reported
in the UK (3), while an increase in the frequency of KD-like has been
reported in Italy (4).
Evaluating clinical models it is clear that:
-Kawasaki disease (KD) is a rare acute pediatric vasculitis with
coronary artery aneurysms as its main complication. The diagnosis is
based on the presence of persistent fever, exanthema, lymphadenopathy,
conjunctival injection, and changes in the mucosae and cutaneous
extremities of hands and feet (5).
-Toxic Shock Syndrome (TSS) is a disease caused by toxins produced by
Staphylococcus Aureus but also related to group A Streptococcus, is
characterized by fever, diffuse macular erythroderma, peeling 1–2 weeks
after getting the rash, hypotension and multisystem implication of three
or more of the following organ systems: gastrointestinal, muscular,
mucous, renal, hepatic, haematological, central nervous system (6).
However, isolation in biological samples of one of the bacteria
mentioned above is necessary to make the diagnosis. It is possible to
hypothesize that SARS-CoV2, alone or in combination, may trigger or
facilitate TSS.
-Secondary Hemophagocytic lymphohistiocytosis (sHLH) is a severe
systemic inflammatory syndrome that can be fatal, often triggered by
infection. The diagnosis is based on a number of clinical signs and
laboratory findings, five out of the following nine diagnostic criteria
must be met: fever, splenomegaly, cytopenias (affecting two or more of
three lineages in the peripheral blood), hypertriglyceridemia,
hypofibrinogenemia, elevated ferritin, hemophagocytosis in bone
marrow/spleen/lymph nodes, low or absent natural killer (NK)-cell
activity, or elevated soluble CD25 (7).
The pediatric cases described during the Covid 19 pandemic, labeled as
atypical KD or hyperinflammatory syndrome, have clinical features and
laboratory tests that are reminiscent of both KD, TSS and sHLH, but do
not fully meet any of the clinical criteria for these diseases.
It is possible to hypothesize that there is a new pediatric pathological
entity characterized by a state of hyperinflammation and manifested by
fever, systemic involvement, gastrointestinal symptoms mostly abdominal
pain, cardiogenic shock due to severe myocarditis and acute kidney
injury. Numerous definitions have been proposed of which pediatric
inflammatory multisystem syndrome (PMIS) temporally associated with
SARS-CoV-2 (8).
PMIS appears to be a postinfectious inflammatory process, suggested by
the fact that it is delayed after the COVID peak, by the negativity of
the nasopharyngeal swab and by the antibody positivity. The
characteristics that allow us to distinguish PMIS from KD are: the
different age group affected, as PIMS mostly affects children with an
average age of 8-10 years including adolescents. Another element of
difference lies in the geography of the affected areas given the less
frequent Chinese cases, despite being the country most affected at the
beginning of the pandemic.
From available clinical data and reports, differences between PMIS and
KD are evident: in KD involvement of the gastrointestinal and renal
systems are uncommon. In addition, to the laboratory tests, it is
possible to find some major analogies between PIMS and sHLH for example
hyperferritinemia, D-dimer increase, and to the cytokine storm of TSS
(9).
Patients have improved coincident with IVIG with or without steroids,
suggesting that this kind of therapy, in KD, TSS and in this new
inflammatory syndrome is effectively modulating cytokine activation.
It is necessary to collect further factors that allow us to better
understand this emerging new hyperinflammatory pathology (PMIS) and its
overlap with other inflammatory disorders (Figure 1). In the meantime
strict medical surveillance is pivotal in order to maintain low the
transmission of Sars-CoV-2 in childhood .
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