Kawasaki disease

Kawasaki disease
Kawasaki disease
Classification and external resources

A child showing characteristic "strawberry tongue" seen in Kawasaki disease
ICD-10 M30.3
ICD-9 446.1
OMIM 611775
DiseasesDB 7121
MedlinePlus 000989
eMedicine ped/1236
MeSH D009080

Kawasaki disease (KD), also known as Kawasaki syndrome, lymph node syndrome and mucocutaneous lymph node syndrome,[1] is an autoimmune disease in which the medium-sized blood vessels throughout the body become inflamed. It is largely seen in children under five years of age. It affects many organ systems, mainly those including the blood vessels, skin, mucous membranes and lymph nodes; however, its rare but most serious effect is on the heart where it can cause fatal coronary artery aneurysms in untreated children. Without treatment, mortality may approach 1%, usually within six weeks of onset. With treatment, the mortality rate is less than 0.01% in the U.S.[2] There is often a pre-existing viral infection that may play a role in its pathogenesis.[3] The conjunctivae and oral mucosa, along with the epidermis (skin), become erythematous (red and inflamed). Edema is often seen in the hands and feet and one or both of the cervical lymph nodes are often enlarged. Also, a remittent fever, often 40°C (104°F) or higher, is characteristic of the acute phase of the disease.[4] In untreated children, the febrile period lasts on average approximately 10 days, but may range from five to 25 days.[4] The disorder was first described in 1967 by Dr. Tomisaku Kawasaki in Japan.[5]

Contents

Classification

Systemic vasculitis is an inflammatory condition affecting both veins and arteries throughout the body, and is usually caused by a proliferation of cells associated with an immune response to a pathogen, or autoimmunity.[6] Systemic vasculitides may be classified according to the type of cells involved in the proliferation, as well as the specific type of tissue damage occurring within the vein or arterial walls.[6] Under this classification scheme for systemic vasculitis, Kawasaki disease is considered to be a necrotizing vasculitis (also called necrotizing angeititis), which may be identified histologically by the occurrence of necrosis (tissue death), fibrosis, and proliferation of cells associated with inflammation in the inner layer of the vascular wall.[6][7] Other diseases featuring necrotizing vasculitis include Polyarteritis nodosa, Wegener's granulomatosis, Henoch-Schönlein purpura and Churg-Strauss syndrome.[6] Kawasaki disease may be further classified as a medium-sized-vessel vasculitis, affecting medium and small sized blood vessels,[8][9][10] such as the smaller cutaneous vasculature (veins and arteries in the skin) that range from 50 to 100µm in diameter.[11][12] KD is also considered to be a primary childhood vasculitis, a disorder associated with vasculitis that mainly affects children under the age of 18.[13][14] A recent, consensus-based evaluation of vasculitides occurring primarily in children resulted in a classification scheme for these disorders, to both distinguish them and suggest a more concrete set of diagnostic criteria for each.[14] Within this classification of childhood vasculitides, Kawasaki disease is, again, a predominantly medium-sized vessel vasculitis.[14]

It is also an autoimmune form of vasculitis,[4] and is not associated with ANCA antibodies, unlike other vasculitic disorders associated with them, such as wegener's granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome.[6][15] This categorization is considered essential for appropriate treatment.[16]

Signs and symptoms

(A) Bilateral, non-exudative conjunctivitis with perilimbal sparing - "conjunctival injection". (B) Strawberry tongue and bright red, swollen lips with vertical cracking and bleeding. (C) Erythematous rash involving perineum. (D) Erythema of the palms, which is often accompanied by painful, brawny edema of the dorsa of the hands. (E) Erythema of the soles, and swelling dorsa of the feet. (F) Desquamation of the fingers. (G) Erythema and induration at the site of a previous vaccination with Bacillus Calmette-Guérin (BCG). (H) Perianal erythematous desquamation.[4]

Kawasaki disease often begins with a high and persistent fever that is not very responsive to normal treatment with paracetamol (acetaminophen) or ibuprofen.[17][18] it is the most prominent symptom in Kawasaki disease, which is a characteristic sign of the acute phase of the disease, is normally high (above 39-40º C), remittent and followed by extreme irritability.[18][19] recent reports says it is even present in patients with atypical or incomplete KD,[20][21]nevertheless recent reports says it is not present on 100% of cases.[22] The first day of fever is considered the first day of illness,[17] and the duration of fever is on average one to two weeks; in the absence of treatment, it may extend for three to four weeks,[4] Prolonged fever is associated with higher incidence of cardiac involvement.[23] It responds partially to antipyretic drugs and does not cease with the introduction of antibiotics.[4] However, when appropriate therapy is started – intravenous immunoglobulin (IVIG) and aspirin – the fever is gone after two days.[24]

Bilateral conjunctival injection was reported by many publications to be the most common symptom after fever,[25][26] it typically involves the bulbar conjunctivae, is not accompanied by suppuration, it is not painful.[27] It usually begins shortly after the onset of fever during the acute stage of the disease.[17] Anterior uveitis may be present on slit-lamp examination.[28][29] iritis can occur too. [30]

Inflammation of the mucous membranes in the mouth,[4] along with erythema (redness), edema (swelling) with fissures (cracks in the lip surface), desquamation (peeling) and exsudation of the lips are also evident. The oropharynx mucosa has enanthema and the tongue maintains an unusual red appearance termed "strawberry tongue" (marked erythema with prominent gustative papillae).[12] Keratic precipitates (detectable by a slit lamp but usually too small to be seen by the unaided eye), and swollen lymph nodes may also be present and can be the first manifestation of the disease.[17][31] Rashes occur early in the disease, and the cutaneous rash observed in patients with KD is non-specific, polymorphic, non-itchy and normally observed up to the fifth day of fever. Cutaneous exanthema may comprise macular-papular erythematous and fissure lesions, the most common type, in addition to urticariform type rash, purpuric, multiform-like erythema.[32] and peeling of the skin in the genital area, hands, and feet (especially around the nails and on the palms and soles) may occur in later phases.[17][33] Some of these symptoms may come and go during the course of the illness. It is a syndrome affecting multiple organ systems, and in the acute stage of KD, systemic inflammatory changes are evident in many organs.[9] Myocarditis,[34] pericarditis, valvulitis, aseptic meningitis, pneumonitis, lymphadenitis, and hepatitis may be present and are manifested by the presence of inflammatory cells in the affected tissues.[9] 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 (heart attack).[12] If treated in a timely fashion, this risk can be mostly avoided and the course of illness cut short.[35]

Less common manifestations
System Manifestations
GIT Diarrhea, abdominal pain, vomiting, liver dysfunction, pancreatitis, Hydrops gallbladder, cholangitis, intussusception, intestinal pseudo-obstruction, ascites, splenic infarction.
MSS Polyarthritis and arthralgia.
CVS Myocarditis, pericarditis, valvular heart disease.
GU Urethritis, prostatitis, cystitis, priapism, Interstitial nephritis, orchitis, nephrotic syndrome.
CNS Aseptic meningitis, and sensorineural deafness.
RS Influenza-like illness, plural effusion, Atelectasis.
Skin Erythema and induration at BCG vaccine site, Beau's lines, and finger gangrene.
Source: review,[12] table.[36]
  • High-grade fever (greater than 39 °C or 102 °F; often as high as 40 °C or 104 °F),[12] The duration of fever is on average one to two weeks; in the absence of treatment, it may extend for three to four weeks.[12] However, when appropriate therapy is started the fever is gone after two days.[17]
  • Red eyes (conjunctivitis) bilateral without pus or drainage, also known as "conjunctival injection".[30]
  • Anterior uveitis.[30]
  • Bright red, chapped, or cracked lips.[12]
  • Red mucous membranes in the mouth.[12]
  • Strawberry tongue, white coating on the tongue or prominent red bumps (papillae) on the back of the tongue.[12]
  • Red palms of the hands and the soles of the feet.[12]
  • Peeling (desquamation) palms and soles (later in the illness); peeling may begin around the nails.[4][17]
  • Rash which may take many forms, non-specific, polymorphic, non-itchy, but not vesicle-bullous lesions, and appears on the trunk.[12]
  • Swollen lymph nodes (frequently only one lymph node is swollen, and is usually on one side), particularly in the neck area.[33]
  • Joint pain (arthralgia) and swelling, frequently symmetrical, Also arthritis can occur.[12]
  • Irritability.[12]
  • Tachycardia (rapid heart beat).[12]
  • Beau's lines (transverse grooves on nails).[12]
  • May find breathing difficult.[12]

Complications

X-ray showing aneurysmal enlargement of the coronary arteries, which is a complication in a Kawasaki syndrome

The cardiac complications are the most important aspect of the disease. Kawasaki disease can cause vasculitic changes (inflammation of blood vessels) in the coronary arteries and subsequent coronary artery aneurysms. These aneurysms can lead to myocardial infarction (heart attack) even in young children. Overall, about 10–18% of children with Kawasaki disease develop coronary artery aneurysms with much higher prevalence among patients who are not treated early in the course of illness. Kawasaki disease and rheumatic fever are the most common causes of acquired heart disease among children in the United States.[37][38]

Causes

Like all autoimmune diseases, the cause of Kawasaki disease is presumably the interaction of genetic and environmental factors, possibly including an infection. The specific cause is unknown,[39][40][41] but current theories center primarily on immunological causes for the disease. Evidence increasingly points to an infectious etiology,[42] but debate continues on whether the cause is a conventional antigenic substance or a superantigen.[43] Children's Hospital Boston reported that "some studies have found associations between the occurrence of Kawasaki disease and recent exposure to carpet cleaning or residence near a body of stagnant water; however, cause and effect have not been established."[38] Other data suggests possible correlation of KD with tropospheric wind patterns

An association has been identified with a SNP in the ITPKC gene, which codes an enzyme that negatively regulates T-cell activation.[44] An additional factor that suggests genetic susceptibility is the fact that regardless of where they are living, Japanese children are more likely than other children to contract the disease.[38] The HLA-B51 serotype has been found to be associated with endemic instances of the disease.[45]

Diagnosis

Criteria for Diagnosis of Kawasaki Disease
Fever of ≥5 days' duration associated with at least 4† of the following 5 changes
Bilateral nonsuppurative conjunctivitis
One of more changes of the mucous membranes of the upper respiratory tract, including pharyngeal injection, dry fissured lips, injected lips, and "strawberry" tongue
One or more changes of the extremities, including peripheral erythema, peripheral edema, periungual desquamation, and generalized desquamation
Polymorphous rash, primarily truncal
Cervical lymphadenopathy >1.5 cm in diameter
Disease cannot be explained by some other known disease process
†A diagnosis of Kawasaki disease can be made if fever and only 3 changes are present in conjunction with coronary artery disease documented by two-dimensional echocardiography or coronary angiography.
Source: Nelson's essentials of pediatrics,[46] Review[14]

Kawasaki disease can only be diagnosed clinically (i.e. by medical signs and symptoms). There exists no specific laboratory test for this condition. It is difficult to establish the diagnosis, especially early in the course of the illness, and frequently children are not diagnosed until they have seen several health care providers. Many other serious illnesses can cause similar symptoms, and must be considered in the differential diagnosis, including scarlet fever, toxic shock syndrome, juvenile idiopathic arthritis, and childhood mercury poisoning (infantile acrodynia).[citation needed]

Classically, five days of fever[47] plus four of five diagnostic criteria must be met in order to establish the diagnosis. The criteria are: (1) erythema of the lips or oral cavity or cracking of the lips; (2) rash on the trunk; (3) swelling or erythema of the hands or feet; (4) red eyes (conjunctival injection) (5) swollen lymph node in the neck of at least 15 millimeters.

Many children, especially infants, eventually diagnosed with Kawasaki disease do not exhibit all of the above criteria. In fact, many experts now recommend treating for Kawasaki disease even if only three days of fever have passed and at least three diagnostic criteria are present, especially if other tests reveal abnormalities consistent with Kawasaki disease. In addition, the diagnosis can be made purely by the detection of coronary artery aneurysms in the proper clinical setting.

Investigations

A physical examination will demonstrate many of the features listed above.

Blood tests

Other optional tests

  • Electrocardiogram may show evidence of ventricular dysfunction or, occasionally, arrhythmia due to myocarditis
  • Echocardiogram may show subtle coronary artery changes or, later, true aneurysms.
  • Ultrasound or computerized tomography may show hydrops (enlargement) of the gallbladder
  • Urinalysis may show white blood cells and protein in the urine (pyuria and proteinuria) without evidence of bacterial growth
  • Lumbar puncture may show evidence of aseptic meningitis
  • Angiography was historically used to detect coronary artery aneurysms and remains the gold standard for their detection, but is rarely used today unless coronary artery aneurysms have already been detected by echocardiography.
  • Temporal artery biopsy

Treatment

Children with Kawasaki disease should be hospitalized and cared for by a physician who has experience with this disease. When in an academic medical center, care is often shared between pediatric cardiology and pediatric infectious disease specialists (although no specific infectious agent has been identified as yet).[38] It is imperative that treatment be started as soon as the diagnosis is made to prevent damage to the coronary arteries.

Intravenous immunoglobulin (IVIG) is the standard treatment for Kawasaki disease[48] and is administered in high doses with marked improvement usually noted within 24 hours. If the fever does not respond, an additional dose may have to be considered. In rare cases, a third dose may be given to the child. IVIG by itself is most useful within the first seven days of onset of fever, in terms of preventing coronary artery aneurysm.

Salicylate therapy, particularly aspirin, remains an important part of the treatment (though questioned by some)[49] but salicylates alone are not as effective as IVIG. 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's 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's syndrome.[50]

Corticosteroids have also been used,[51] 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.[52] Additionally, corticosteroid use in the setting of Kawasaki disease is associated with increased risk of coronary artery aneurysm, and 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.

There are also treatments for iritis and other eye symptoms. Another treatment may include the use of Infliximab (Remicade). Infliximab works by binding tumour necrosis factor alpha.[53]

Prognosis

With early treatment, rapid recovery from the acute symptoms can be expected and the risk of coronary artery aneurysms 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. Overall, about 2% of patients die from complications of coronary vasculitis. Patients who have had Kawasaki disease should have an echocardiogram initially every few weeks, and then every one or two years to screen for progression of cardiac involvement.

It is also not uncommon that a relapse of symptoms may occur soon after initial treatment with IVIG. This usually requires re-hospitalization and re-treatment. Treatment with IVIG can cause allergic and non-allergic 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 non-treatment. There is also evidence that Kawasaki disease produces altered lipid metabolism that persists beyond clinical resolution of the disease.

Epidemiology

Kawasaki disease affects boys more than girls with people of Asian ethnicity, particularly Japanese and Korean people are most susceptible as well as people of Afro-Caribbean ethnicity. The disease was rare in Caucasians until the last few decades and incidence rate fluctuates from country to country.

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 <5 years of age (~1 in 450 children). At this present attack rate, more than 1 in 150 children in Japan will develop Kawasaki disease during their lifetime.

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. Approximately 2,000-4,000 cases are identified in the United States each year.[37][38]

In the United Kingdom, estimates of incidence rate vary because of the rarity of Kawasaki disease. However, Kawasaki disease is believed to affect fewer than 1 in every 25,000 people.[54] Incidence of the disease doubled from 1991 to 2000 however, with 4 cases in per 100,000 children in 1991 compared with a rise of 8 cases per 100,000 in 2000.[55]

History

The disease was first reported by Dr. Tomisaku Kawasaki in a four-year-old child with a rash and fever at the Red Cross Hospital in Tokyo, Japan in January of 1961, and later published a report on 50 similar cases.[56]Later Yamamoto and colleagues were persuade that there is definite cardiac involvement when they studied and reported 23 cases, of which 11(48%) patients had abnormalities detected by an electrocardiogram.[57] It was not until 1974 that the first description of this disorder was published in the English language literature.[58]in the year 1976 Melish et al., described the same illness in 16 children in Hawaii.[59]Melish and Kawasaki had independently developed the same diagnostic criteria for the disorder, which are still used today to make the diagnosis of classic KS.

A question was raised whether the disease only started during the period between 1960 and 1970, but later a preserved heart of a 7 year old boy died in 1870 was examined and showed three aneurysms of the coronary arteries with clots, as well as pathologic changes consistent with KS.[60] KS is now recognized worldwide. In the United States and other developed nations, it appears to have replaced acute rheumatic fever as the most common cause of acquired heart disease in children.[61]

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  • Kawasaki disease — This disease has nothing to do with the motor bike of the same name. It is a syndrome of unknown origin that mainly affects young children, causing fever, reddening of the eyes (conjunctivitis), lips and mucous membranes of the mouth, ulcerative… …   Medical dictionary

  • Kawasaki disease — noun a disease in young children with an unknown cause, giving rise to a rash, glandular swelling, and sometimes damage to the heart. Origin 1960s: named after the Japanese physician Tomisaku Kawasaki …   English new terms dictionary

  • Kawasaki disease — mucocutaneous lymph node syndrome a condition of unknown cause affecting young children, usually less than five years old, and characterized by fever, conjunctivitis, a sore throat, and a generalized rash and reddening of the palms and soles.… …   The new mediacal dictionary

  • Kawasaki disease — /kawəˈsaki dəziz/ (say kahwuh sahkee duhzeez) noun a rare but serious autoimmune disease of small children, causing blood vessel inflammation in many organs in the body. Also, Kawasaki syndrome, lymph node syndrome …   Australian-English dictionary

  • Kawasaki disease — noun Etymology: Tomisaku Kawasaki b1925 Japanese pediatrician Date: 1977 an acute illness of unknown cause that chiefly affects infants and children and is characterized especially by fever, rash, conjunctivitis, inflammation of lips and tongue,… …   New Collegiate Dictionary

  • Kawasaki disease — noun an acute disease of young children characterized by a rash and swollen lymph nodes and fever; of unknown cause • Syn: ↑mucocutaneous lymph node syndrome • Hypernyms: ↑disease …   Useful english dictionary

  • Kawasaki disease — Pathol. an acute illness of unknown cause, occurring primarily in children, characterized by high fever, swollen lymph glands, rash, redness in mouth and throat, and joint pain. [1980 85; after Japanese pediatrician Tomisaku Kawasaki, who first… …   Universalium

  • Kawasaki disease — n. acute vasculitis that occurs mainly in children under 5 years of age that was first described in the late 1960 s by a Japanese pediatrician named Tomisaku Kawasaki that can cause coronary artery aneurysms or heart attacks and sudden death in… …   English contemporary dictionary

  • Kawasaki disease — Acute inflammatory disease with systemic angiitis, most commonly occurring in infants and young children. Cause uncertain …   Dictionary of molecular biology

  • Kawasaki disease — noun an illness of childhood that causes fever, lymphadenopathy, elevated platelet count, and a variety of other symptoms. Syn: Kawaski syndrome, lymph node syndrome, mucocutaneous lymph node syndrome …   Wiktionary

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