Kawasaki disease

Overview

Kawasaki disease (KD) is a self-limiting pediatric systemic vasculitis with a preference for the coronary arteries. KD mostly affects children between the ages of 6 months and 4 years. Asians have up to a 20-fold greater incidence rate than Caucasians. The cause of KD is unknown. One plausible open hypothesis is that KD is caused by an infectious pathogen that causes an autoimmune illness exclusively in people who are genetically susceptible to it.

A young kid with KD often has a high swinging fever for five or more days that persists after antibiotic and/or antipyretic therapy. The lips are cracked and dry. There is a strawberry tongue and generalized erythema of the oropharyngeal mucosal surfaces. Lymphadenopathy is almost often unilateral and limited to the anterior cervical triangle.

Coronary aneurysms most commonly occur during the convalescence period (beginning during the second week). Because there are no laboratory tests for KD, the diagnosis is determined only on the presence of a constellation of clinical symptoms. Echocardiography is used to determine the existence of coronary artery dilatation or aneurysm development. Most individuals with acute KD can benefit from effective therapy, although the precise mechanisms of action are unknown.

Aspirin and intravenous immunoglobulins (IVIG) are first-line treatments. For the children who do not respond to this medication, there are other possibilities, although they are not as effective. Some hospitals try to save refractory individuals by administering intravenous pulsed doses of methylprednisolone. Other clinics utilize infliximab or a mix of these treatments.

Kawasaki disease (KD) definition

Kawasaki disease (KD), also known as mucocutaneous lymph node syndrome, is a self-limiting, acute medium vessel vasculitis with a preference for the coronary arteries. It is the primary cause of acquired heart disease in affluent countries, and it is gradually displacing rheumatic heart disease in developing countries.

The illness most commonly affects children under the age of five. When signs of Kawasaki illness are detected early and treated, children tend to feel better within a few days.

Kawasaki disease causes

The cause of Kawasaki disease (KD) is unknown, however it might be caused by a wind-borne or water-borne virus. However, in recent years, research has revealed specific genetic markers. In fact, siblings are 10-20 times more likely than the overall population to have the condition.

There is no indication that the illness spreads from person to person. Multiple species of bacterial and viral origin have been suspected as a cause, but no one agent has been established as the primary cause to far. However, research suggests that more than 40% of children with KD tested positive for viral respiratory infections.

Pathophysiology

This condition is most frequent in children under the age of five, but it can occur at any age, including adults. A minor masculine preponderance exists (male to female ratio = 1.5 to 1). Boys are also more likely to die as a result of problems. It is unusual to observe Kawasaki illness in children under the age of four months, which may be due to maternal antibodies.

It is more prevalent in Asian children, particularly Japanese children, and is least common in Caucasian children. The condition also appears to be more prevalent in the winter and spring months. In the United States and Canada, the incidence ranges from 10 to 20 per 100,000 children aged 5 to 50 to 250 per 100,000 in Japan, Taiwan, or Korea.

Kawasaki disease symptoms

These youngsters will have a fever and nonspecific malaise for many days. A physical exam will frequently reveal one or more of the diagnostic criteria mentioned below. It is critical to obtain a complete history since satisfying any of the diagnostic criteria at any point throughout the illness contributes to the diagnosis of Kawasaki disease, even if they are not present at the time of examination. The illness process is divided into three stages: acute, subacute, and convalescent.

The acute phase is characterized by a sudden onset of a high fever that lasts 1 to 2 weeks but can last up to 3 to 4 weeks if ignored. Conjunctivitis and myocarditis develop during the acute phase of the rash. When the fever fades, the subacute phase begins and lasts until weeks 4 to 6 of the illness course.

Desquamation of the hands, thrombocytosis and the formation of coronary artery aneurysms will occur in the patient. The convalescent phase begins when the clinical indications of the illness stop, which usually occurs within 3 months after the disease's beginning. Cardiac anomalies can still be seen at this time, however, new aneurysms after 8 weeks of sickness are uncommon.

A variety of less common manifestations include:

• Abdominal pain, 
• Vomiting, or diarrhea in 20% of cases;
• Hepatitis; 
• Parotitis;
• Intussusception; 
• Joint pain in 15-50% of cases, especially the larger weight-bearing joints; 
• Headache, 
• Irritability, 
• Seizure, 
• Aseptic meningitis; 
• Rhinorrhea and
• Cough in 20-30% of cases; 
• Aortic aneurysms; valvular insufficiency; 

The American Heart Association (AHA) issued the criteria for establishing a diagnosis in 2014. It is crucial to note, however, that children who do not fit the entire criteria yet exhibit cardiac abnormalities on echocardiography are diagnosed with KD. The patient must have had fevers for five days or more, with at least four of the following requirements met (either all at once or over a period of days):

• Bilateral bulbar conjunctival injection without exudate is painless.
• Strawberry tongue, erythematous mouth, and pharynx, or red, cracked lips
• Exanthem polymorphous (morbilliform, maculopapular, or scarlatiniform)
• Hand and foot swelling with erythema of the palms and soles
• Lymphadenopathy of the cervix (over 1.5 cm in diameter)

Patients often have a patchy widespread macular erythematous rash across the trunk and extremities that emerge within 5 days after the fever and resembles a viral exanthem or drug eruption but lacks pruritus. Patients with KD will also often have peeling of the skin in the periungual region, which begins around 2 to 3 weeks following the beginning of fever.

Diagnosis

Kawasaki disease is diagnosed clinically. The most common symptom is fever, which is only mildly responsive to antipyretics and frequently persists over 38.5 degrees Celsius. A conjunctival injection can also cause photophobia and is associated with uveitis in around 65 percent of patients. All of these symptoms appear consecutively, indicating the presence of KD above other disease processes in the differential. Complete KD should be diagnosed during the acute phase of the disease. 

Kawasaki disease diagnostic criteria 

Fever for > 5 days and :

• Conjunctivitis without exudate
• Rash
• Edema or erythema of hands or feet, followed by desquamation and nail changes
• Adenopathy, often unilateral, cervical node > 1.5 cm 
• Mucosal erythema, fissures or crusting of lips or strawberry tongue
• Fever for > 5 days
• Enanthem of mucosal membranes
• Bulbar conjunctivitis
• Rash, erythematous, polymorphous
• Internal organ involvement: coronary, abdominal, pneumonitis, hepatitis, orchitis
• Extremity changes, initial edema, erythema, desquamation, nail changes

In children with five-day fevers and two or three of the key criteria, incomplete Kawasaki illness should be considered. It is more frequent in older children and younger newborns. As a result, if a child less than 6 months has a protracted fever lasting more than 7 days, and echocardiography should be performed to rule out KD. For these individuals, the AHA has developed a protocol that includes lab tests and echocardiography to make the diagnosis.

If the C-reactive protein (CRP) level is 30 mg/l and the erythrocyte sedimentation rate (ESR) is 40 mm/hr, then monitor the patient daily; if the fever goes away and the skin peels, have echocardiography and treat any aneurysms found. If the CRP is greater than 30 mg/l and/or the ESR is greater than 40 mm/hr, echocardiography should be performed. More than three of the following must be present in order to fulfill partial KD criteria, commence therapy, and undergo an echocardiogram:

• Hemoglobin low for age
• White blood count (WBC) > 15,000/mm
• Platelet count > 450,000/mm
• Serum albumin < 3.0 g/dl
• Elevated alanine aminotransferase
• Urine WBC > 10/high-power field 

Except for echocardiography, no additional laboratory or diagnostic imaging procedures are required following a clinical diagnosis of KD. Some investigations, however, may be beneficial in the event of partial illness to assist limit the diagnosis when not satisfying all of the clinical criteria. Complete blood count (CBC), metabolic panel, ESR, CRP, and urinalysis are all suggested tests.

The acute disease phase is characterized by mild-moderate normocytic anemia, whereas the subacute phase is characterized by thrombocytosis. Thrombocytopenia may be present in the acute phase less frequently, but it predicts a higher risk of coronary artery aneurysm (CAA) and may be linked with immune thrombocytopenic purpura (ITP), disseminated intravascular coagulation (DIC), or immunoglobulin degradation.

Hypoalbuminemia is possible and is associated with a more severe and protracted illness course. Hepatic obstruction can produce hyperbilirubinemia and increased liver enzymes, which can lead to obstructive jaundice and gallbladder hydrops.

 The levels of acute-phase reactants are virtually invariably increased. In individuals, less than 3 months old, pro-B-type natriuretic peptide (Pro-BNP) levels appear to be associated with an increased risk of coronary artery aneurysm development and intravenous immunoglobulin (IVIG) resistance. Urinalysis will reveal sterile pyuria, which will not be present if the sample was obtained using bladder aspiration.

To rule out a coronary artery aneurysm, echocardiography should be conducted during the acute phase of the condition (CAA). The most typically impacted arteries are the proximal left anterior descending and right coronary arteries. Fusiform, saccular, ectatic, and segmentation aneurysms are all possible. Fusiform, tiny, and distal aneurysms are more prone to regress.

Other areas of the heart must also be evaluated for evidence of aortic root dilatation, reduced contractility, valve dysfunction, and effusion. Ultrasound, on the other hand, is limited by operator skill and has trouble analyzing the mid and distal portions of the veins. As a result, CTA of the coronary arteries is becoming more popular since it can precisely identify and quantify lesions, particularly those in the mid and distal portions of the vessels.

However, the dangers and benefits of radiation exposure in the pediatric population must be weighed. Furthermore, CT has limitations in assessing the lumen of arteries with calcification. Some researchers are currently employing electron beam CT to detect coronary artery calcifications as a predictor of future coronary events.

If radiation exposure is a problem, magnetic resonance angiography (MRA) is another method that is more sensitive for tiny lesions and intimal hyperplasia. Electrocardiography (ECG) can reveal a prolonged PR interval, deep Q waves, low voltage, ST-T shifts, and arrhythmias indicative of myocardial injury and repolarization problems

Management

Treatment for Kawasaki disease tries to reduce the likelihood of coronary artery aneurysm (CAA) development, which occurs two to four weeks after illness onset, by reducing coronary artery inflammation. Supportive treatment is also necessary. Patients should be given high dosage IVIG at 2 g/kg as well as high dose aspirin (80 mg/kg/day to 100 mg/kg/day) until they have been afebrile for at least 48 hours.

At that point, ASA should be continued, but the dose should be reduced to 3 mg/kg-5 mg/kg and maintained until there is no sign of cardiac abnormalities, which should be around 6 to 8 weeks from sickness beginning. Although ASA is thought to modify platelet activity by reducing inflammation and avoiding thrombosis, there is no evidence that it truly inhibits the development of CAA.

Because of hypoalbuminemia, short stomach transition time, and rapid renal clearance, which causes toxic effects at lower dosages, there has been some new worry about ASA administration in the acute phase of the condition. It is also worth noting that children are more likely to develop Reye syndrome if they get influenza or varicella while taking ASA, thus children should have the influenza vaccination but not the varicella vaccine while using ASA. Clopidogrel or dipyridamole can be used as substitutes for ASA allergy, or to avoid Reye syndrome temporarily during influenza or varicella sickness.

If the patient remains febrile 36 to 48 hours following the initial IVIG dosage, the dose should be repeated. To avoid potential cardiac problems, IVIG should be begun within 7-10 days following the beginning of fever. There is evidence that pre-IVIG IgG levels correlate with susceptibility to treatment as well as cardiac outcomes. 

There has been some worry regarding high-dose IVIG (4g/kg vs. 2g/kg) causing hemolytic anemia, with patients with full KD who were resistive to IVIG and non-O-blood types being the most sensitive. Infliximab at 5 mg/kg or cyclophosphamide are two more IVIG possibilities. Keep in mind that IVIG might cause infusion responses, and that pretreatment or availability to resuscitative medicines may be required. Also, keep in mind that IVIG might cause inefficient immunization, so routine vaccinations (such as MMR) may need to be delayed.

Corticosteroids, in addition to IVIG and ASA, have been advocated as part of the first treatment due to results of a lower risk of developing cardiac problems. However, study findings have proved inconclusive. There has been no evidence that corticosteroids are dangerous, and they may be used as a treatment alternative at the discretion of the treating physician.

Due to their immunomodulatory properties, some have proposed statins for KD; however, there is not enough research at this time to suggest their use; the theory is that their ability to target endothelial dysfunction would make them useful during the acute phase to help prevent and/or modify vessel changes.

Furthermore, there is some evidence that ARBs and statins have an additive impact in preventing atherosclerotic disease. Plasma exchange treatment has been shown to be beneficial in lowering the occurrence of Coronary Artery Aneurysm in patients who are unresponsive to IVIG; however, this has only been studied in limited case series and uncontrolled clinical studies and is not currently recommended.

Patients with substantial perfusion deficits caused by an aneurysm may require coronary artery bypass graft surgery, which should be considered in children with reversible ischemia or patients with repeated MIs. Percutaneous intervention frequently fails because of the severity of the illness and substantial constriction of the arteries, putting the patient at increased risk of new aneurysm development or perforation.

Long-term therapy begins after the acute sickness has subsided, which is usually 5-6 weeks after the first beginning of the fever; this is usually when coronary artery involvement reaches its highest intensity. The frequency of follow-ups, treatment, and repeat imaging is determined by the severity of the patient's ailment.

Platelet activity stays high for 3 months to a year after illness start, and patients should be on low-dose anti-platelet medication for 3 months. Long-term therapy's overall objective is to avoid myocardial ischemia and infarction. Complete remission of coronary artery lesions has been documented in over 50% of patients 1 to 2 years after disease onset, and appears to be depending on the size of the original lesion.

Prognosis

The severity of the heart illness determines the prognosis. Furthermore, children diagnosed between the ages of 6 months and 9 years have a better prognosis than those diagnosed younger or older, possibly because they are identified early after presenting with typical symptoms. 

Recurrence is rare, however it is more prevalent in younger children who have cardiac problems from the illness during the original episode. All KD-related fatalities are mostly the consequence of cardiac problems and generally occur 15-45 days after fever starts.

Complications

The condition can cause aneurysms, heart failure, MI, myocarditis, valvulitis, pericarditis with pericardial effusion, and coronary artery rupture, resulting in hemopericardium and sudden death. Acute phase cardiac issues affect around 9% of individuals, whereas cardiac sequelae affect approximately 3%. Patients with Kawasaki illness typically get MIs when sleeping or resting, indicating a coronary vasospasm origin. 

Myocardial inflammation has been observed in 50 to 70% of patients during the acute phase of the illness, raising concerns about the long-term implications of KD on heart function. Mitral regurgitation and aortic regurgitation have been documented in a limited proportion of children with KD. CAAs will affect around 15-25 percent of untreated youngsters. A number of variables contribute to an increased risk of coronary artery aneurysms, including:

• Fever >8 days (most important risk factor)
• Recurrence of fever after a period of being afebrile for 48 hours
• Male (3 times more likely to develop giant aneurysms)
• Cardiomegaly
• <1 year old of age
• Asian or Pacific Islander descent
• Hispanic ethnicity
• Lower IgG levels
• Increased pro-BNP levels
• Increased TNF-alpha levels
• Thrombocytopenia at initial presentation
• Incomplete Kawasaki Disease Diagnosis 

Aneurysms are defined as vessel diameters more than 3mm in children under the age of 5, and greater than 4mm in children above the age of 5. Cardiac issues later in life have been demonstrated to be more likely in persons with CAAs greater than 6.0mm. Giant aneurysms (>8.0mm) are more likely to occlude due to a thrombus during the first year, resulting in a MI.

There will be substantial thickening of the artery in individuals whose aneurysms clear, increasing the risk of early coronary atherosclerotic disease. There was no indication of a residual aneurysm in a study of people who experienced a MI later in life after having had a coronary artery aneurysm as a kid owing to KD. However, just because an aneurysm dissolve does not indicate that the danger of heart problems later in life is eliminated.

Conclusion 

Although Kawasaki illness is an uncommon sickness, it is best addressed by an interprofessional team due to its devastating consequences on the coronaries. When a child is suspected of having Kawasaki disease, he or she should be referred to a cardiologist as soon as possible.

A cardiologist should be consulted to decide the initial and subsequent echocardiography examinations, anticoagulation therapy, if coronary artery angiography is required, and for long-term follow-up and monitoring. In addition, an infectious disease expert, rheumatologist, or dermatologist should be considered.

Kawasaki disease treatment, includes the use of infliximab, etanercept, and anakinra. Infliximab was observed to reduce inflammatory markers (TNF) and downregulate macrophages in patients with IVIG resistant KD, and patients had a faster fever resolution but identical cardiac outcomes.

Following therapy, the short-term prognosis is favorable, but the long-term prognosis is uncertain, owing to the large number of children who are lost to follow-up.

An investigational experiment comparing IVIG alone to IVIG plus infliximab for the first treatment of children with KD has also been conducted. Children who got the combined therapy were shown to be less resistive to treatment, to have shorter fever duration and hospital admissions, and to have less coronary artery dilatation.

In addition, their lab abnormalities reverted to normal values in a shorter period of time. However, there was no difference between the two groups in the actual incidence of coronary aneurysms. Plasma exchange therapy has also been examined as a viable therapy for individuals who are resistant to IVIG treatment, and it has shown promise by improving and/or resolving cardiac abnormalities during follow-up.