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Kawasaki Disease

Disease Details

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Description: Kawasaki disease is an illness primarily affecting children that causes inflammation of blood vessels throughout the body and can lead to complications in the heart.
Type: Kawasaki disease is an autoimmune condition. Its exact cause is unknown, but it is not considered to be inherited in a traditional genetic manner. Rather, it is believed to result from a combination of genetic susceptibility and environmental factors.
Signs And Symptoms: Kawasaki disease often begins with a high and persistent fever that is not very responsive to normal treatment with paracetamol (acetaminophen) or ibuprofen. This is the most prominent symptom of Kawasaki disease, and is a characteristic sign that the disease is in its acute phase; the fever normally presents as a high (above 39–40 °C) and remittent, and is followed by extreme irritability. Recently, it is reported to be present in patients with atypical or incomplete Kawasaki disease; nevertheless, it is not present in 100% of cases.The first day of fever is considered the first day of the illness, and its duration is typically one to two weeks; in the absence of treatment, it may extend for three to four weeks. Prolonged fever is associated with a higher incidence of cardiac involvement. It responds partially to antipyretic drugs and does not cease with the introduction of antibiotics. However, when appropriate therapy is started – intravenous immunoglobulin and aspirin – the fever subsides after two days.Bilateral conjunctival inflammation has been reported to be the most common symptom after fever. It typically involves the bulbar conjunctivae, is not accompanied by suppuration, and is not painful. This usually begins shortly after the onset of fever during the acute stage of the disease. Anterior uveitis may be present under slit-lamp examination. Iritis can occur, too. Keratic precipitates are another eye manifestation (detectable by a slit lamp, but are usually too small to be seen by the unaided eye).Kawasaki disease also presents with a set of mouth symptoms, the most characteristic of which are a red tongue, swollen lips with vertical cracking, and bleeding. The mucosa of the mouth and throat may be bright red, and the tongue may have a typical "strawberry tongue" appearance (marked redness with prominent gustative papillae). These mouth symptoms are caused by necrotizing microvasculitis with fibrinoid necrosis.Cervical lymphadenopathy is seen in 50% to 75% of children, whereas the other features are estimated to occur in 90%, but sometimes it can be the dominant presenting symptom. According to the diagnostic criteria, at least one impaired lymph node ≥ 15 mm in diameter should be involved. Affected lymph nodes are painless or minimally painful, nonfluctuant, and nonsuppurative; erythema of the neighboring skin may occur. Children with fever and neck adenitis who do not respond to antibiotics should have Kawasaki disease considered as part of the differential diagnoses.

In the acute phase of the disease, changes in the peripheral extremities can include erythema of the palms and soles, which is often striking with sharp demarcation and often accompanied by painful, brawny edema of the dorsa of the hands or feet, so affected children frequently refuse to hold objects in their hands or to bear weight on their feet. Later, during the convalescent or the subacute phase, desquamation of the fingers and toes usually begins in the periungual region within two to three weeks after the onset of fever and may extend to include the palms and soles. Around 11% of children affected by the disease may continue skin-peeling for many years. One to two months after the onset of fever, deep transverse grooves across the nails may develop (Beau's lines), and occasionally nails are shed.The most common skin manifestation is a diffuse macular-papular erythematous rash, which is quite nonspecific. The rash varies over time and is characteristically located on the trunk; it may further spread to involve the face, extremities, and perineum. Many other forms of cutaneous lesions have been reported; they may include scarlatiniform, papular, urticariform, multiform-like erythema, and purpuric lesions; even micropustules were reported. It can be polymorphic, not itchy, and normally observed up to the fifth day of fever. However, it is never bullous or vesicular.In the acute stage of Kawasaki disease, systemic inflammatory changes are evident in many organs. Joint pain (arthralgia) and swelling, frequently symmetrical, and arthritis can also occur. Myocarditis, diarrhea, pericarditis, valvulitis, aseptic meningitis, pneumonitis, lymphadenitis, and hepatitis may be present and are manifested by the presence of inflammatory cells in the affected tissues. If left untreated, some symptoms will eventually relent, but coronary artery aneurysms will not improve, resulting in a significant risk of death or disability due to myocardial infarction. If treated quickly, this risk can be mostly avoided and the course of illness cut short.
Other reported nonspecific symptoms include cough, rhinorrhea, sputum, vomiting, headache, and seizure.The course of the disease can be divided into three clinical phases.
The acute febrile phase, which usually lasts for one to two weeks, is characterized by fever, conjunctival injection, erythema of the oral mucosa, erythema and swelling of the hands and feet, rash, cervical adenopathy, aseptic meningitis, diarrhea, and hepatic dysfunction. Myocarditis is common during this time, and a pericardial effusion may be present. Coronary arteritis may be present, but aneurysms are generally not yet visible by echocardiography.
The subacute phase begins when fever, rash, and lymphadenopathy resolve at about one to two weeks after the onset of fever, but irritability, anorexia, and conjunctival injection persist. Desquamation of the fingers and toes and thrombocytosis are seen during this stage, which generally lasts until about four weeks after the onset of fever. Coronary artery aneurysms usually develop during this time, and the risk for sudden death is highest.
The convalescent stage begins when all clinical signs of illness have disappeared, and continues until the sedimentation rate returns to normal, usually at six to eight weeks after the onset of illness.Adult onset of Kawasaki disease is rare. The presentation differs between adults and children: in particular, it seems that adults more often have cervical lymphadenopathy, hepatitis, and arthralgia.Some children, especially young infants, have atypical presentations without the classic set of symptoms. Such presentations are associated with a higher risk of cardiac artery aneurysms.
Prognosis: With early treatment, rapid recovery from the acute symptoms can be expected, and the risk of coronary artery aneurysms is greatly reduced. Untreated, the acute symptoms of Kawasaki disease are self-limited (i.e. the patient will recover eventually), but the risk of coronary artery involvement is much greater, even many years later. Many cases of myocardial infarction in young adults have now been attributed to Kawasaki disease that went undiagnosed during childhood. Overall, about 2% of patients die from complications of coronary vasculitis.Laboratory evidence of increased inflammation combined with demographic features (male sex, age less than six months or greater than eight years) and incomplete response to IVIG therapy create a profile of a high-risk patient with Kawasaki disease. The likelihood that an aneurysm will resolve appears to be determined in large measure by its initial size, in which the smaller aneurysms have a greater likelihood of regression. Other factors are positively associated with the regression of aneurysms, including being younger than a year old at the onset of Kawasaki disease, fusiform rather than saccular aneurysm morphology, and an aneurysm location in a distal coronary segment. The highest rate of progression to stenosis occurs among those who develop large aneurysms. The worst prognosis occurs in children with giant aneurysms. This severe outcome may require further treatment such as percutaneous transluminal angioplasty, coronary artery stenting, bypass grafting, and even cardiac transplantation.A relapse of symptoms may occur soon after initial treatment with IVIG. This usually requires rehospitalization and retreatment. Treatment with IVIG can cause allergic and nonallergic acute reactions, aseptic meningitis, fluid overload, and rarely, other serious reactions. Overall, life-threatening complications resulting from therapy for Kawasaki disease are exceedingly rare, especially compared with the risk of nontreatment. Evidence indicates Kawasaki disease produces altered lipid metabolism that persists beyond the clinical resolution of the disease.Rarely, recurrence can occur in Kawasaki disease with or without treatment.
Onset: Kawasaki disease typically has an acute onset and primarily affects children under the age of 5. The onset includes a high and persistent fever lasting more than five days, which is often unresponsive to standard fever medications.
Prevalence: Kawasaki disease is relatively rare, primarily affecting children under 5 years old. The prevalence varies globally; it's most common in Japan, with an incidence of about 150 to 200 per 100,000 children under 5. In the United States, the incidence is approximately 25 per 100,000 children under 5.
Epidemiology: Kawasaki disease affects boys more than girls, with people of Asian ethnicity, particularly Japanese people. The higher incidence in Asian populations is thought to be linked to genetic susceptibility. Incidence rates vary between countries.
Currently, Kawasaki disease is the most commonly diagnosed pediatric vasculitis in the world. By far, the highest incidence of Kawasaki disease occurs in Japan, with the most recent study placing the attack rate at 218.6 per 100,000 children less than five years of age (about one in 450 children). At this present attack rate, more than one in 150 children in Japan will develop Kawasaki disease during their lifetimes.However, its incidence in the United States is increasing. Kawasaki disease is predominantly a disease of young children, with 80% of patients younger than five years of age. About 2,000–4,000 cases are identified in the U.S. each year (9 to 19 per 100,000 children younger than five years of age). In the continental United States, Kawasaki disease is more common during the winter and early spring, boys with the disease outnumber girls by ≈1.5–1.7:1, and 76% of affected children are less than 5 years of age.In the United Kingdom, prior to 2000, it was diagnosed in fewer than one in every 25,000 people per year. Incidence of the disease doubled from 1991 to 2000, however, with four cases per 100,000 children in 1991 compared with a rise of eight cases per 100,000 in 2000. By 2017, this figure had risen to 12 in 100,000 people with 419 diagnosed cases of Kawasaki disease in the United Kingdom.In Japan, the rate is 240 in every 100,000 people.Coronary artery aneurysms due to Kawasaki disease are believed to account for 5% of acute coronary syndrome cases in adults under 40 years of age.
Intractability: Kawasaki disease is generally not considered intractable. It is an acute, self-limiting vasculitis that primarily affects children. With timely diagnosis and appropriate treatment, most children recover fully. The standard treatment includes intravenous immunoglobulin (IVIG) and aspirin to reduce inflammation and prevent complications such as coronary artery aneurysms. Early intervention is crucial to minimize the risk of long-term cardiac issues.
Disease Severity: Kawasaki Disease is a serious condition that primarily affects children under the age of 5. It causes inflammation in the walls of some blood vessels in the body, including the coronary arteries, which supply blood to the heart muscle. If left untreated, it can lead to significant complications, including coronary artery aneurysms, heart muscle inflammation, and heart valve problems. Early diagnosis and treatment are crucial to reduce the risk of serious complications.
Healthcare Professionals: Disease Ontology ID - DOID:13378
Pathophysiology: Kawasaki disease is primarily an inflammatory condition affecting the medium-sized arteries throughout the body, particularly the coronary arteries. The exact pathophysiology remains unclear, but it is believed to involve an abnormal immune response triggered by an infectious agent in genetically predisposed children. This immune response leads to widespread inflammation of the blood vessels (vasculitis).

The immune activation involves cytokine release and infiltration of various immune cells, such as T-cells, macrophages, and neutrophils, into the vascular tissues. This inflammation can cause endothelial cell dysfunction and damage to the arterial walls, leading to the formation of aneurysms, particularly in the coronary arteries, which can result in serious cardiac complications.
Carrier Status: Carrier status is not applicable to Kawasaki disease. Kawasaki disease is an acute, self-limited vasculitis that primarily affects young children. The exact cause is unknown, but it is not a hereditary or communicable disease, and thus does not have carriers.
Mechanism: Kawasaki disease (KD) is an acute, self-limited vasculitis predominantly affecting children. The exact mechanism remains unclear, but it is believed to involve an interplay between genetic susceptibility and environmental triggers, possibly infections.

**Mechanism:**
1. **Immune Activation:** An abnormal immune response to an environmental trigger leads to widespread inflammation.
2. **Vascular Inflammation:** The primary pathology involves inflammation of medium-sized arteries, particularly the coronary arteries.
3. **Cytokine Storm:** Excessive production of pro-inflammatory cytokines like TNF-α, IL-6, and IL-1β.
4. **Endothelial Damage:** Inflammation damages the endothelial cells lining the blood vessels, leading to aneurysms or stenosis.

**Molecular Mechanisms:**
1. **Genetic Factors:** Polymorphisms in genes related to immune response (e.g., ITPKC, CASP3) can predispose individuals to KD.
2. **Innate Immunity:** Overactivation of pathways like the TLR (Toll-like receptor) and NLR (NOD-like receptor) families initiates an intense inflammatory response.
3. **Adaptive Immunity:** Activation of T-cells and B-cells produces autoantibodies and further perpetuates vascular inflammation.
4. **Endothelial Injury:** Dysfunctional endothelial cells release vasoactive substances and attract immune cells, exacerbating vascular damage.

Understanding these mechanisms helps in the diagnosis and treatment of Kawasaki disease, though ongoing research is essential to fully elucidate its pathogenesis.
Treatment: Children with Kawasaki disease should be hospitalized and cared for by a physician who has experience with this disease. In an academic medical center, care is often shared between pediatric cardiology, pediatric rheumatology, and pediatric infectious disease specialists (although no specific infectious agent has yet been identified). To prevent damage to coronary arteries, treatment should be started immediately following the diagnosis.Intravenous immunoglobulin (IVIG) is the standard treatment for Kawasaki disease and is administered in high doses with marked improvement usually noted within 24 hours. If the fever does not respond, an additional dose may be considered. In rare cases, a third dose may be given. IVIG is most useful within the first seven days of fever onset, to prevent coronary artery aneurysm. IVIG given within the first 10 days of the disease reduces the risk of damage to the coronary arteries in children, without serious adverse effects. A 2023 systematic review and meta-analysis revealed that no prediction models of IVIG resistance in patients with Kawasaki disease could accurately distinguish the resistance.Salicylate therapy, particularly aspirin, remains an important part of the treatment (though questioned by some) but salicylates alone are not as effective as IVIG. There is limited evidence to indicate whether children should continue to receive salicylate as part of their treatment. Aspirin therapy is started at high doses until the fever subsides, and then is continued at a low dose when the patient returns home, usually for two months to prevent blood clots from forming. Except for Kawasaki disease and a few other indications, aspirin is otherwise normally not recommended for children due to its association with Reye syndrome. Because children with Kawasaki disease will be taking aspirin for up to several months, vaccination against varicella and influenza is required, as these infections are most likely to cause Reye syndrome.High-dose aspirin is associated with anemia and does not confer benefit to disease outcomes.About 15-20% of children following the initial IVIG infusion show persistent or recurrent fever and are classified as IVIG-resistant. While the use of TNF alpha blockers (TNF-α) may reduce treatment resistance and the infusion reaction after treatment initiation, further research is needed. Due to the potential involvement of the upregulated calcium-nuclear factor of activated T cells pathway in the development of the disease, a 2019 study found that the combination of ciclosporin and IVIG infusion can suppress coronary artery abnormalities. Further research is needed to determine which patients would respond best to this treatment.Corticosteroids have also been used, especially when other treatments fail or symptoms recur, but in a randomized controlled trial, the addition of corticosteroid to immune globulin and aspirin did not improve outcome. Additionally, corticosteroid use in the setting of Kawasaki disease is associated with increased risk of coronary artery aneurysm, so its use is generally contraindicated in this setting. In cases of Kawasaki disease refractory to IVIG, cyclophosphamide and plasma exchange have been investigated as possible treatments, with variable outcomes. However, a Cochrane review published in 2017 (updated in 2022) found that, in children, the use of corticosteroids in the acute phase of KD was associated with improved coronary artery abnormalities, shorter hospital stays, a decreased duration of clinical symptoms, and reduced inflammatory marker levels. Patient populations based in Asia, people with higher risk scores, and those receiving longer steroid treatment may have greater benefit from steroid use.
Compassionate Use Treatment: Kawasaki disease primarily requires timely treatment with intravenous immunoglobulin (IVIG) and aspirin to reduce the risk of coronary artery abnormalities. For compassionate use and off-label or experimental treatments, some options include:

1. **Corticosteroids**: Used in cases resistant to IVIG or as adjunctive therapy in severe cases.
2. **Infliximab**: A monoclonal antibody against tumor necrosis factor-alpha (TNF-α) that has been used in IVIG-resistant Kawasaki disease.
3. **Anakinra**: An interleukin-1 receptor antagonist, used experimentally for severe or IVIG-resistant cases.
4. **Cyclosporine**: An immunosuppressant considered in refractory cases of Kawasaki disease.
5. **Methotrexate**: Used in certain cases based on an experimental basis, particularly in recurrent Kawasaki disease.

These treatments are generally considered for use when standard therapy fails or when patients have severe forms of the disease.
Lifestyle Recommendations: Lifestyle recommendations for Kawasaki disease primarily focus on supporting recovery and managing symptoms during and after treatment:

1. **Medication Adherence**: Ensure the child takes all prescribed medications, such as aspirin or intravenous immunoglobulin (IVIG), as directed by the healthcare provider.

2. **Regular Medical Check-ups**: Schedule follow-up appointments to monitor heart health, especially since Kawasaki disease can affect the coronary arteries.

3. **Healthy Diet**: Provide a balanced diet rich in fruits, vegetables, whole grains, and lean proteins to support overall health and recovery.

4. **Hydration**: Encourage adequate fluid intake to help manage fever and reduce the risk of dehydration.

5. **Rest and Recuperation**: Ensure the child gets plenty of rest, especially during the acute phase of the illness.

6. **Activity Limitations**: Follow medical advice regarding physical activity, particularly if there are any concerns about the heart.

7. **Oral Hygiene**: Maintain good oral hygiene to prevent infections, which can impact overall health and recovery.

8. **Emotional Support**: Offer emotional support and comfort to the child, as Kawasaki disease can be a stressful experience for both the child and the family.

9. **Education and Awareness**: Educate yourself and caregivers about the signs and symptoms of potential complications, such as heart issues, and when to seek medical attention.

10. **Infection Prevention**: Practice good hand hygiene and avoid exposure to contagious illnesses to reduce the risk of infections, which can complicate recovery.

These recommendations aim to support the child’s health during recovery and help prevent complications associated with Kawasaki disease. Always consult with healthcare providers for personalized advice.
Medication: Kawasaki disease is treated with a combination of medications to reduce inflammation and prevent heart complications. The primary medications used include:

1. Intravenous immunoglobulin (IVIG): This is the main treatment and is usually administered in a single high dose. It helps reduce inflammation and the risk of coronary artery aneurysms.
2. Aspirin: High-dose aspirin is initially given to reduce inflammation and fever. Once the fever subsides, low-dose aspirin is continued for several weeks to prevent blood clots.
3. Corticosteroids: In cases where the disease does not respond to IVIG and aspirin, corticosteroids like prednisone may be used.

Management and follow-up care are essential to monitor for potential heart issues.
Repurposable Drugs: Kawasaki disease is a condition that primarily affects children and involves inflammation of the blood vessels. There are no widely recognized repurposable drugs specifically for Kawasaki disease, as the standard treatment typically includes intravenous immunoglobulin (IVIG) and aspirin. Research is ongoing, and some potential treatments being explored include corticosteroids and anti-inflammatory medications like infliximab or cyclosporine, though these are not yet established as standard for repurposing in Kawasaki disease.
Metabolites: Kawasaki disease is not primarily characterized by specific metabolites in medical literature. It is an acute, self-limited vasculitis that primarily affects children under the age of 5. While routine laboratory tests might show elevated inflammatory markers such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), there isn't a direct association with specific metabolites. Further research might be needed to explore potential metabolic markers, but none are currently well-established.
Nutraceuticals: There is limited scientific evidence supporting the use of nutraceuticals specifically for the treatment of Kawasaki disease. It is primarily treated with high-dose intravenous immunoglobulin (IVIG) and aspirin to reduce inflammation and prevent coronary artery aneurysms. Always consult with a healthcare provider before considering alternative treatments.
Peptides: Kawasaki disease primarily affects children and involves inflammation of the blood vessels. While peptides are not the main focus in the treatment or research of Kawasaki disease, understanding immune responses and inflammatory processes, which can involve cytokines (proteins) and peptides, is important. As of now, specific peptide therapies are not a standard part of Kawasaki disease treatment. The main treatment includes intravenous immunoglobulin (IVIG) and aspirin.