Kawasaki Disease: A Ticking Time Bomb

Abstract
Kawasaki disease is an acute, febrile, usually terminal sickness of infancy and childhood. 80%
of the patients affected are younger than four years of age. There is inflammation of mainly the
large and medium-sized vessels. Its clinical significance stems from the involvement of coronary
arteries and their inflammatory changes. Coronary inflammation leads to aneurysms that rupture
or cause thrombosis, leading to infarction. In genetically predisposed individuals, a variety of
infectious agents (mostly viral) trigger this malady. The characteristic redness might result from
a delayed-type hypersensitivity response directed against cross-reactive or newly uncovered
antigen(s). Subsequent macromolecule production and polyclonal white blood cell activation
result in autoantibodies to epithelium cells and sleek muscle cells that further precipitate the
redness. Kawasaki disease’s clinical manifestations range from oral skin disease to the
blistering of the mucosa, symptoms involving the hands and the feet, skin disease of the palms
and soles, a desquamative rash, and cervical lymphatic tissue enlargement (so it is also
referred to as tissue layer lymphatic tissue syndrome). Approximately two-hundredths of
untreated patients develop some vessel sequelae, starting from well-organized coronary
inflammation, to severe arterial blood vessel dilatation, to large artery aneurysms (7-8
millimeters in diameter) with rupture or occlusion, infarction, and thrombosis. With human
gamma globulin administration, good standards of medical care, and the use of analgesics, the
speed of symptomatic progression and inflammatory artery changes are reduced.
Keywords: Kawasaki, Strawberry Tongue, Rash, Inflammation, Japan

Methods:
Search strategy and selection criteria
References for this comprehensive review were taken by searches of PubMed, Google Scholar,
Scopus, and Cochrane Library between January 1989 and December 2021, and references from
relevant articles. The search terms “Kawasaki”, “Strawberry Tongue”, “Rash”, “Inflammation”,
and “Japan” were used. There were no language restrictions.

Ethics Approval: N/A

Role of Funding Sources: Nil
1) Introduction
Kawasaki disease (KD) was first identified in 1967 by Dr. Tomisaku Kawasaki as a natural
lymphoid tissue syndrome. It is an acute, end, systematic inflammation of unknown causes that
happens predominantly in infants and young youngsters. KD is markedly seen in plenty in
Japan, where 264.8/1,000,000 youngsters aged below 5 years were treated in 2012. The
foremost necessary complication of KD is artery abnormalities that occur in exactly two-fifth of
untreated patients.[1] KD designation patterns put together demonstrate seasonality, with its
incidence peaks variable depending on the population studies. Notably, seasonal peaks of this
illness usually correspond to winter/spring, once metabolic infectious agent infections square up
during these seasons. On a population level, the incidence rate of KD in Japanese populations
is ~330 per 100,000 youngsters aged 0–4 years annually and the United States reports a
hospitalization rate of ~20 per 100,000 youngsters aged 0–4 years annually. Children of Asian
and Pacific descent individuals living in the United States are affected at an intermediate rate,
whereas on the prime side lies the White population in the United States and Asian children
living in Japan. Any racial background or any genetic setting, therefore, is vulnerable to
influencing the pathogenesis of KD.[2]
2) Epidemiology
In Japan, nationwide surveys have been conducted since 1970 for the incidence and
prevalence of KD. The age distribution at the onset of KD shows a peak at 9–11 months, and a
seventieth of all KD happens in patients younger than three years old. In keeping with the most
recent survey, the full variety of registered patients is found to be larger than 2,40,000. The
quantity of KD patients has been increasing in kids in Japan. Additionally, the subsequent were
processed by the surveys with the findings: (i) nationwide epidemics have existed thrice within
the past; (ii) though there has been no nationwide epidemic recently, there's a tiny low epidemic
in a very restricted region and it's moving to the adjacent region; (iii) the quantity of patients
increases in winter and reduces in summer; and (iv) the chance of generation of the disease in
the siblings is considerably higher than that in non-siblings. The incidence in kids aged less than
five years is 220/100 000 in Japan and one hundred in the peninsula. The incidence is 10–20
times on top of that in western countries. In keeping to a report from Hawaii, the USA the mean
rate in Hawaii is forty. However the rate clearly differs by race; which is 360 for Japanese,
ninety-five for Chinese, seventy-seven for Hawaiians, fifty-six for Filipino, and seven for
Caucasians. This information recommends that the status of KD depends a lot upon racial
factors than geographic ones. Additionally, the relative risk for siblings is concerning ten times
higher and a recent study has discovered that second-generation KD patients exist a lot more
typically than expected. Identification of genetic factors associated with individual status or
completely different incidences among ethnicities may give a key to the determination of the
mystery of KD. [3] The rate of the second-case malady of Kawasaki disease/ mucocutaneous
lymph node syndrome occurring among 1788 siblings of kids with the disease was derived from
information obtained from questionnaires armored to the members of the Japanese Association
of fogeys of kids with the syndrome. At intervals of one year when the onset of the primary case
in a very family occurred, the general second-case rate was 2.1% for siblings, as compared to
the associated overall incidence of roughly 0.19% within the general population of kids zero to
four years in Japan within the epidemic year 1982. For siblings younger than one year, it was
8.4%, and for those between one and a couple of years old, it was 9.3%. Over 54.1% of the
second cases developed ten days or less when the primary cases occurred. [4]
3) Discussion

3.1) Pathogenesis
Each racial/ genetic background and setting seem to cause a sturdy influence on the event of
KD. Environmental and alternative triggered the KD in one study of 169 kids in the urban center
county. Climatic factors looked as if they would play a part too, higher precipitation and lower
temperatures were related to a higher incidence of KD. These same associations were
confirmed within the Japanese population exploitation nationwide survey information over a
period of thirteen years, which allowed the authors to regulate for alternative seasonality factors.
Tropospheric wind patterns have conjointly been connected to KD, with giant shifts in a pattern
reminiscent of peaks in KD incidence. A follow-up study steered that, specifically, easterly winds
arising from northern China might carry plant life species or alternative environmental toxins that
would trigger KD. After several thoughts of traditional background pathology yet as potential
contamination with this sensitive technique, four patients were determined to own proof of virus
infection probably relevant to KD. The infections known were: bocavirus, rhinovirus, infantile
paralysis virus, and contagion virus. Genome-wide association studies have greatly dilated the
number of factor variants connected to KD. These findings have, in turn, allowed new insights
into KD pathogenesis. In one of the most important social cohort studies, for instance, 2
susceptibleness loci were known, together with one polymorphism within the FCGR2A factor.
This factor encodes the FcγRIIA receptor, a low-affinity receptor for the Ig Fc. FcγRIIA is
expressed in a good form in immune cells, particularly the phagocytes. Completely different
polymorphisms in FCGR2A have afterward been connected to KD susceptibleness in several
ethnic groups. The association of FCGR2A with risk for KD is particularly fascinating given the
role of IV IG in KD treatment, as the mechanism of IV IG efficaciousness in KD continues to be
not understood completely. Notably, high FcγRIIA messenger RNA expression levels square
measure related to IVIG resistance. The second loci known during this study concerned ITPKC,
a factor antecedently related to KD susceptibleness by linkage analysis in an exceedingly
Japanese cohort. The ITPKC factor encodes for B-1,4,5-triphosphate-3-kinase C, an associate
in Nursing protein that negatively regulates the Calcium response in immune cells. Within the
early section of the health problem (approximately initial 10 days), mixed inflammatory infiltrates
with neutrophils, eosinophils, macrophages, and lymphocytes are seen involving the tissue layer
of the most important coronary arteries. The media is comparatively spared. Perivasculitis
involving the microvessels and blood vessels conjointly characterize this intense inflammatory
stage. [5]
3.2) Immune response
The reaction related to the disease is advanced and involves the activation and infiltration of the
arterial blood vessel wall by each innate and reconciling immune cell. On the idea of studies of
post-mortem tissue from patients with this disease, a tube-shaped structure pathology has been
classified into 3 sequent connected with the pathological processes. Necrotizing redness
develops within the initial two weeks of the illness and is related to neutrophil infiltrations that
step by step destroy the arterial blood vessel tissue layer, media, and a few parts of the deeper
tissue layer. [6] However, during a series of six specimens, leucocyte infiltration was quickly
followed by white blood cell infiltrates, then mixed white blood cell and plasmacytic infiltrates
were incontestable later, close to day nineteen of the disease. Distinguished nodular infiltrates,
the same as induration of the arteries plaque formation, have additionally been delineated,
however, these seem to occur at later time points (>3 weeks). These infiltrates consisted of T
cells, macrophages, B cells, and prevailing IgM+ plasma cells, with less frequent IgA+ plasma
cells. [7]
Strong support exists for the activation of the lymphokine (IL-1) pathway in KD because of the
abundance of IL-1-related genes, and higher levels of IL-1 pathway proteins in plasma. In KD, a
pair of dominant protein clusters are recognized: the IL-6/T helper TH-17 axis and also the IL-
12/interferon-gamma axis. IL-6, together with remodeling protein beta (TGFβ), polarizes naïve T
cells toward a Th-17 makeup, leading to these cells invading the vessel wall and causing an
unhealthy protein profile. [8] CD4:CD8 ratio of 2.3–2.7 in the peripheral blood in acute KD
indicates a striking reversal of the CD4:CD8 ratio in the primary target tissue of this illness. [9]
3.3) Symptoms
Kawasaki disease (KD) is diagnosed once a patient runs a fever of a minimum of 100.4°F for a
minimum of 5 days. If the fever isn’t treated, it can last up to eleven days. The fever is in the
midst of a minimum of four of the subsequent symptoms:
i) A rash over the body and the extremities.
ii) Redness and swelling of the palms and soles of the feet occur. Peeling of the skin on
the fingertips and toes happens within the second and third weeks.
iii) Bloodshot eyes that may be sensitive to light.
iv) Fluid-filled swollen glands within the neck and mensuration over 1.5 centimeters,
typically the neck feels stiff.
v) Irritation and inflammation of the mouth, lips, and throat. “Strawberry” tongue is
characteristic – the tongue is jolting and red with enlarged style buds.
Patients might experience abdominal pain. Considerably a small fraction of them develops
temporary inflammatory disease with pain and swelling of the knee and the hip. Incomplete
disease ought to be thought about if a baby has fever and inflammation while not all the
other symptoms are present. [10] Bilateral Non-exudative conjunctivitis can also be seen. [11]

Figure 1: Diagnostic Features of Kawasaki Disease

3.4) Complications
i) Inflammation of the heart muscle (myocarditis), lining of the valves (endocarditis), or
covering of the valves (pericarditis).
 ii) Heart failure
iii) Kawasaki disease may additionally have an effect on different body systems as well
like CNS, RS, Musculoskeletal, etc.
iv) Coronary artery aneurysms, calcifications, stricture, and incompetence due to
scarring of the leaflets or progressive artery root dilatation. [12]
v) Coronary artery occlusion by thrombosis. [13]
3.5) Diagnosis
A healthcare professional should examine the kid and observe the signs and symptoms
characteristic of KD. Blood tests and other serological tests can also be done to rule out
alternative diseases and appearance for inflammation, however, these tests aren't specific for
KD. A USG imaging can offer a transparent image of the coronary arteries and the way the
valves are functioning. This might aid in the identification of the illness. [14]
3.6) Treatment
The current guidelines to manage mucocutaneous lymph node syndrome indicate the use of
high-dose IV IG. If given throughout the primary ten days of the illness, IV IG reduces the
chance of development of coronary rubor and aneurysms. The mechanisms by which the IV IG
treatment reduces the inflammatory responses is still unknown, but, it is suspected to possess a
wide spectrum of action targeting multiple pathways of the immune response. IV IG has been
shown to inhibit IL-1β production from in vitro aroused macrophages and to stimulate the
assembly of IL-1Ra. throughout mucocutaneous lymph node syndrome. It also reduces the
production of pro-inflammatory cytokines and chemokines and reduces the activation of
neutrophils, monocytes, macrophages, and T cells by saturating Fc receptors. [15],[16] The use of
clarithromycin and endogenous antibody in a study showed that clarithromycin reduces the
relapse rate of KD. Clarithromycin appeared effective in reducing KD relapse by inhibiting the
discharge of the bioactive molecules via its anti-biofilm effect. Therefore, clarithromycin could be
effective not only in patients suffering from the acute course of KD but also in their siblings to
prevent the illness from developing in them.[17]
In a study of 2 groups, one with an anti-TNF compound combined with IV IG and another with IV
IG alone showed fewer refractory KD patients within the combined treatment cluster than within
the IV IG alone cluster. KD patients within the combined treatment cluster had higher outcomes
with shorter fever durations and hospital stays, as well as less artery dilation. [18] Clopidogrel
combined with a low-dose anodyne is safe and effective in antithrombotic medical care for kids
with KD. [19] The potential advantage of the above medication and immunomodulatory actions of
a lipid-lowering medicine showed that kids with acute mucocutaneous lymph node syndrome
and early signs of coronary artery injury can get benefit from the addition of the lipid-lowering
medicine to plain medical care. [20]
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