​Kembara Xtra - Medicine - Kawasaki Disease

​Kembara Xtra - Medicine - Kawasaki Disease 
The majority of patients with Kawasaki syndrome (KS), a self-limited acute, febrile, systemic vasculitis of small- and medium-sized arteries, are between the ages of 6 months and 5 years.
 The leading factor behind childhood acquired coronary artery disease in industrialized nations.
- Aneurysms and ectasia caused by vasculitis of the coronary arteries can cause myocardial infarction (MI), ischemia, or sudden death. - Affected organ systems include the cardiovascular, gastrointestinal, hematologic/lymphatic/immunologic, musculoskeletal, nervous, pulmonary, renal/urologic, skin/exocrine, and musculoskeletal disorders.

Any child with an extended high fever that is not responding to antibiotics or antipyretics, a rash, and nonexudative conjunctivitis should be given caution KS.

All races are affected, although Asia has the highest incidence rates; in Japan, the annual incidence rate for children under the age of five is 265/100,000.
The annual incidence in children under the age of five is 19/100,000 in the United States. African Americans have a 1.5 times higher risk than Caucasians, whereas Asian Americans have a 2.5 times higher risk. Hawaii has the highest state incidence rate.
Leading contributor to childhood heart disease in developed nations
- The median age of diagnosis is 1.5 years old. The predominant age range is 1 to 5 years.
- Children under the age of five make up 85% of cases, and children under two make up 50%.
- The ratio of men to women is 1.5:1.

Asians have a higher prevalence than Black Americans, Hispanics, and Caucasians do. Seasonal variations include peaks in winter and early spring (January to March) in temperate regions and summer in Asia. Outbreaks occur every two to three years.

Pathophysiology and Etiology 
Children with a genetic predisposition experience an inappropriate inflammatory response to an infectious pathogen.
Particularly in coronary arteries, acute KS results in a necrotizing arteritis in the smooth muscle layer of medium extraparenchymal arteries, eroding artery walls into the adventitia.
As the acute process resolves, active neutrophilic inflammatory cells are followed by a subacute/chronic, lymphocytic vasculitis; fibroblasts and monocytes cause tissue repair/remodeling that may result in vascular fibrosis and stenosis. Inflammatory cells secrete cytokines (TNF-), interleukins 1 and 6, and matrix metalloproteases that cause fragmentation of the internal elastic lamina.
Genetics
Higher risk populations and familial ties imply a genetic predisposition.
In Japan, siblings of patients have a 10- to 30-fold increased risk of developing KS, and more than 50% do so within 10 days after the initial case; KS is more common in children whose parents also had the disease when they were children.
SNPs in six distinct genes (Fc receptor 2A, CASP3, HLA class II, B-cell lymphoid kinase, IPTKC, and CD40) have been linked to KS.
TGF-signaling pathway variations are linked to coronary aneurysms.

Male to female predominance in the United States is 1.5:1, with Black Americans at 1.5 times risk and Asian Americans at 2.5 times risk. Another risk factor is having a sibling with Kawasaki.No safeguards are available.

Diagnosis: 4 of the 5 main clinical characteristics listed below and 5 days of fever, OR 4 features with the presence of coronary artery disease on 2D echocardiography:
- Bilateral, limbic-sparing injection of the conjunctiva that is not purulent
- Erythematous changes to the lips, tongue, pharynx, and throat
Changes in the skin of the peripheral extremities (edema of hands/feet; erythema of palms/soles; desquamation of fingers/toes) - A polymorphous, widespread, erythematous rash
- Cervical lymphadenopathy (at least one node with a diameter of 1.5 cm)
Note: If a patient has more than four primary clinical characteristics, a diagnosis can be made on day four of a fever, particularly if there is redness or swelling in the hands or feet.


Child Safety Considerations
Clinicians may think that a subsequent rash is the result of a medication reaction if an extended fever without rash is treated with antibiotics.
Incomplete KS (atypical KS) is defined as having a fever for five days, two to three main clinical characteristics, test results that indicate systemic inflammation, and the exclusion of other disorders.
- Infants younger than six months old or older kids and teenagers are frequently the victims of incomplete instances that meet four clinical criteria. Coronary artery aneurysms (CAAs) are more frequent in patients who had delayed or missed diagnoses. Therefore, take into account echocardiography and inflammatory labs in newborns with protracted fever and few or no clinical symptoms.

Fever is the first symptom of the acute phase, and while symptoms don't always appear at once, they do so frequently.

clinical assessment 
A high-spiking, intermittent fever lasting around 5 days that is insensitive to antibiotics or antipyretics and is a fever of 102-105°F (39.4–40.5°C).
– Extreme irritation is a common characteristic, and the duration can continue up to 10 to 12 days, with more uncommon cases extending 3 to 4 weeks.
 Conjunctival injection that is bilateral, painless, nonpurulent, and free of edema or corneal ulcers. Typically, limbic sparing is observed.
Lips and oral cavity changes include redness and swelling in the acute stage and cracking, fissuring, and bleeding in the subacute stage.
- Strawberry-colored tongue
Within 5 days of fever, there will be an extensive erythematous polymorphous rash; the most typical type is morbilliform. Occasionally micropustular, maculopapular, scarlatiniform, and resembling erythema multiforme, erythroderma, and urticarial exanthem
– Desquamation of the perineum, especially in the skin folds
Extremity alterations include painful induration, swollen hands and feet from days 4 to 7, as well as reddened palms and soles on days 3 to 5.
Acute, unilateral cervical lymphadenopathy (least common symptom) - Desquamation of fingers and toes that starts in the periungual area at 2 to 3 weeks
- One lymph node measuring above 1.5 cm, firm, nonfluctuating, and typically without or barely sensitive.


 Tachycardia, gallop rhythms, hyperdynamic precordium, benign flow murmurs, and reduced contractility were found during the cardiac exam.
Cardiovascular: myocarditis, pericarditis (typically asymptomatic), CAAs, and other medium-sized artery aneurysms are a few more organ systems that may be involved.
- Digestive: anorexia, pain in the abdomen, nausea, acute gallbladder hydrops, enlarged liver, and jaundice
- Renal: sterile pyuria, proteinuria
- Neurologic: irritability, aseptic meningitis, peripheral neuropathy (unilateral facial palsy), transitory high-frequency hearing loss. - Joints: polyarthritis of small joints in acute phase; weight-bearing joints affected after 10th day from beginning of fever.

Differential Diagnosis Bacterial: scarlet fever, bacterial cervical lymphadenitis, Mycoplasma infection, leptospirosis, Lyme disease, Rocky Mountain spotted fever Toxin-mediated: staphylococcal scalded-skin syndrome, streptococcal scarlet fever, toxic shock syndrome Viral: measles, adenovirus, Epstein-Barr virus, SARS-CoV-2 - Multisystem 

Laboratory Results 
Leukocytosis (12,000 to 40,000 cells/mm3) with immature and mature granulocytes is a symptom of meningitis, and an initial workup should include a CBC with differential, urine (UA)/culture, blood culture, and lumbar puncture if the patient is under 90 days old. Anemia should be normochromic and normocytic.
- Thrombocytosis in the second and third weeks (500,000 to >1,000,000/mm3). CAA and MI are linked to acute phase thrombocytopenia.
 Elevated C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and 1-antitrypsin (>35 mg/L in 80%, 60%, and 40%, respectively)
After day 7, normal ESR, CRP, and PLT results point to a diagnosis other than KS.

Caution 

After receiving intravenous immunoglobulin (IVIG) therapy, ESR may be unnaturally elevated.
H. Hyponatremia
 Decreased albumin and protein levels Moderately raised AST, ALT, GGT, and bilirubin levels
CSF pleocytosis (lymphocytic with normal protein and glucose) may be observed.
Although there is no recognized cut-off point, N-terminal brain natriuretic peptide levels may be raised in the acute phase.
Sterile pyuria but no suprapubic collection was observed
Initial tests (lab, imaging) using a nasal swab to rule out adenovirus and coronavirus (SARSCoV- 2)
 If KS is suspected, get an echocardiography and ECG.
– Arrhythmias, a protracted PR interval, and ST/T wave alterations can all be seen on the ECG.
– The right coronary artery may exhibit perivascular brightening, ectasia, impaired left ventricular contractility, pericardial effusion, or aneurysms. Echocardiography has a high sensitivity and specificity for detecting anomalies in the proximal left main coronary artery.
Once aneurysmal advancement stops, repeat echocardiogram at a frequency specified by the severity of aberrant or significant findings should be done twice weekly.
Baseline chest x-ray results may demonstrate pleural effusion, atelectasis, and congestive heart failure (CHF). Cardiac stress test if CAA is detected on echocardiography.
Gallbladder hydrops can either be asymptomatic or linked with abdominal pain.

Other/Diagnostic Procedures

A diagnosis is based on a constellation of clinical symptoms and the exclusion of other disorders; no laboratory testing can provide a diagnosis.
Magnet resonance imaging Patients with complex coronary artery lesions (CALs) may benefit from coronary angiography after the acute inflammatory process has subsided; generally advised in 6 to 12 months. Coronary angiography is a noninvasive modality to visualize coronary arteries for stenosis, thrombi, and intimal thickening.

Management 

Use antibiotics up until bacterial etiologies (such sepsis or meningitis) are ruled out.
Medication 
The best course of treatment is IVIG 2 g/kg IV over 10 to 12 hours with high-dose aspirin, preferably within 7 to 10 days of fever, then low-dose aspirin until subsequent echocardiograms show no evidence of coronary anomalies.
- IVIG may shorten the length of a fever and reduce the incidence of CAA.
– After receiving IVIG, the severe irritation frequently goes away quite soon.
3-5% of kids receiving IVIG experience the development of CALs. Up to 25% of children who go untreated get CALs.
Retreatment with IVIG is necessary if the clinical response is insufficient or if the fever persists or returns more than 36 hours after the commencement of IVIG treatment; around 10% of patients do not react to the first IVIG treatment. The second IVIG dose works on two thirds of nonresponders.
Nonresponders frequently have aberrant echocardiograms, bands, and albumin levels.
 IVIG therapy is followed by four doses of 80 to 100 mg/kg of aspirin per day. When afebrile for 48 to 72 hours, switch to low-dose aspirin (3 to 5 mg/kg/day), or continue taking it until day 14 of the illness. Until the follow-up echocardiography is normal and the CRP and/or ESR are normal, keep the dose low for 6 to 8 weeks. In children with coronary anomalies, keep up the salicylate regimen for a long time or until aneurysm regression is proven.
Aspirin doesn't seem to lower CAA.
Corticosteroids' effectiveness is disputed by available research, and
- Should only be used in cases of IVIG resistance; not as first-line therapy for all KS patients. Aspirin and IVIG should be administered together as the first line of treatment to reduce the likelihood of CAAs in patients who are most at risk of IVIG failure.
IgA insufficiency, anti-IgE/IgG antibodies, severe thrombocytopenia, and coagulation problems are among the contraindications to IVIG.
- Aspirin: proven hypersensitivity, bleeding issues, liver damage, vitamin K insufficiency, hypoprothrombinemia

 Safety measures
- There are no statistically significant differences between the various IVIG preparations.
– Tinnitus, a decline in renal function, and an increase in transaminases can all be side effects of high-dose aspirin therapy.
– Children with CAAs who are taking aspirin for its antiplatelet effects shouldn't take ibuprofen.
Significant potential interactions include the following: Aspirin medication has been linked to Reye syndrome in children who contract viral illnesses, particularly influenza B and varicella. Therefore, yearly influenza vaccine is advised for kids who need to take aspirin for a prolonged period of time. Do not administer any live vaccines for 11 months following IVIG therapy.

Initial Line

Upon a confirmed diagnosis, high-dose IVIG and aspirin should be started right away.

Consider infliximab or cyclosporine in patients who are unresponsive to IVIG and steroids. Plasma exchange may reduce the risk of CAA in IVIG non-responders.

If there are any anomalies on the echocardiography or if there is significant stenosis, consult a pediatric cardiologist.

Further Treatments 
It's important to treat and prevent thrombosis.
Depending on the severity of CAAs, antiplatelet medications (clopidogrel, dipyridamole), heparin, low-molecular-weight heparin, or warfarin may be added to the low-dose aspirin regimen.
In combination with IVIG, clarithromycin may shorten hospital stays and recurrence rates but not fever duration or cardiac outcomes.

Surgical Techniques 
For significant obstruction/recurrent MI, coronary artery bypass grafting is a rare but necessary procedure. The death rate is higher in younger patients.
 Percutaneous coronary intervention for patients who exhibit signs of ischemia during stress testing to revascularize their coronaries

Admission 
Normal saline (NS) for rehydration and half NS for maintenance; discharge if afebrile following a 24-hour IVIG infusion.


Take Action 
Contact and high-risk sports should be avoided when one has aneurysms.
patient observation
 An echocardiography and ECG are repeated in 6 to 8 weeks. Repeat if abnormal at 6 to 12 months.
Patients with complex CALs may need antithrombotic treatment in addition to -blockers to reduce oxidative stress (1). These individuals will need regular monitoring and may benefit from coronary angiography in 6 to 12 months.
Patients on long-term ASA who have not had all recommended vaccinations should do so. Measles and varicella vaccinations are not advised for 11 months following the infusion of IVIG for Kawasaki disease.


The prognosis for moderate-sized aneurysms is typically self-limited and wholly dependent on the extent and severity of heart illness. In 50–66% of instances, this happens within 1–2 years.
Recurrence (3% in Japan and 1% in the US)
Early adulthood sudden death (rare)


Complications 
2-7% of treated patients experience aneurysm development while 15-25% of untreated patients experience CAAs during the convalescent phase. 1% experience massive aneurysms.
Male, 1 year old, ESR >4 weeks, fever >2 weeks, fever >48 hours after IVIG treatment are aneurysm risk factors. Cardiac illness is the cause of 0.08–0.17% of deaths.

---