Kawasaki disease Flashcards
Provide a brief description of kawasaki disease. Where is it the most common vasculitis. What is the etiology
Kawasaki disease (KD, previously called mucocutaneous lymph node syndrome) is one of the most common vasculitides of childhood, particularly in East Asia. It is typically a self-limited condition, with fever and other acute inflammatory manifestations lasting for an average of 12 days if not treated. The underlying etiology is unknown.
What are some of the cardiovascular complications of kawasaki disease?
- coronary artery aneurysms
- cardiomyopathy with depressed myocardial contractility and heart failure
- myocardial infarction
- arrhythmias
- peripheral arterial occlusion
- These complications may cause significant morbidity and mortality, particularly in children who are inadequately treated. The frequency of aneurysm development and mortality has dramatically decreased as a result of intravenous immune globulin therapy. Early diagnosis is critical to achieve the optimal treatment result.
Describe the epidemiology of Kawasaki disease
- Greatest incidence in East Asia or Asian ancestry living in other parts of the world
- Boys are affected more commonly than girls
- 80-90% of cases occur in kids < 5 years old
- Uncommon in kids < 6 months
- Occurrence beyond late childhood is rare
Describe the etiology of Kawasaki disease
Unknown etiology
Infection by one or more agents that usually cause an asymptomatic or nonvasculitic condition in most children but results in KD in genetically predisposed individuals fits the epidemiologic data well
What vessels are affected in kawasaki disease
KD is a systemic, inflammatory illness that particularly affects medium-sized arteries, especially the coronary arteries
How does blood vessel damage occur in kawasaki disease?
Blood vessel damage appears to result from inflammatory cell infiltration into vascular tissues
The stimulus for this infiltration is unknown, but it is most profound in the coronary arteries and can involve destruction of luminal endothelial cells, elastic lamina, and medial smooth muscle cells in severe cases
Inflammatory cells infiltrating the coronary arteries can include neutrophils, T cells (particularly CD8 T cells), eosinophils, plasma cells (particularly immunoglobulin A [IgA] producing), and/or macrophages. Macrophages are not prominent participants in any other type of vasculitis
How does aneurysm formation occur in kawasaki disease?
The destruction of elastin and collagen fibers and loss of structural integrity of the arterial wall lead to dilatation and aneurysm formation
Are neutrophilic infiltrates involved in kawasaki disease?
Yes. A neutrophilic infiltrate is observed in the arterial wall in fatalities that occur within the first two weeks after fever onset and may represent an innate immune response
Are antibodies/immune complexes involved in the pathogenesis of kawasaki disease?
Plasma cells producing oligoclonal IgA antibodies are found in the arteries and respiratory tract of children with KD
Immune complexes are sometimes detected in the peripheral blood in KD, but they are not observed to form deposits in affected tissues and do not appear to correlate with the development of coronary artery disease
Describe the supporting points for the theory of an infectious etiology for kawasaki disease
Many epidemiologic data suggest that KD is caused or triggered by a transmissible agent or agents. Support for this theory is derived from the following similarities between KD and other pediatric infectious conditions:
●KD is characterized by a febrile exanthem with lymphadenitis and mucositis. These are features similar to those of contagious diseases, such as adenovirus infection, measles, and scarlet fever.
●There is a seasonal increase in disease incidence in the winter and summer in many geographic areas.
●The disease often occurs in epidemics, and a geographic wave-like spread of illness during epidemics has been noted.
●Boys are more susceptible than girls. In general, the “set-point” of the immune system varies between genders, leading to an overall higher incidence and morbidity of a variety of infections in males (eg, meningitis , Campylobacter enteritis) and a higher incidence of autoimmune diseases in females.
●Siblings of children with KD in Japan are at increased risk for developing the disease, which usually occurs within one week of onset of the index case.
●The disease is common among children younger than five years but rare in those younger than six months. The rarity in infants may be explained by transfer of passive immunity to the relatively common infectious trigger(s) by transplacentally acquired maternal antibodies.
●There is spatial and temporal clustering of cases
Describe the genetic factors/genes which may be involed in having increased susceptibility to Kawasaki disease?
●Inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) gene on chromosome 19q13.2 . ITPKC acts as a negative regulator of T cell activation, which includes transcription of interleukin 2 (IL-2). The single nucleotide polymorphism (SNP) associated with KD susceptibility results in a weaker inhibitory effect upon T cell activation. Patients with this SNP may have a more vigorous T cell response during an inflammatory disease, such as KD, compared with those without this allelic change. However, this polymorphism is not common enough even in the Japanese population to explain the vast majority of cases of KD.
●Angiopoietin 1 (ANGPT1) and vascular endothelial growth factor A (VEGFA) genes. Expression of angiopoietin 1 is upregulated and VEGF is downregulated in patients with acute versus convalescent KD, suggesting disruption of vascular homeostasis.
●The genes encoding the chemokine receptor CCR5 and its major ligand CCL3L1.
●The adenosine triphosphate (ATP)-binding cassette, subfamily C, member 4 (ABCC4) gene. ABCC4 is a cyclic nucleotide transporter involved in migration of dendritic cells and cellular efflux of prostaglandin.
GWAS have revealed other potential susceptibility loci, including a functional polymorphism in the immunoglobulin G receptor gene (FCGR2A). In addition to being a putative susceptibility factor, ITPKC is associated with an increased risk of coronary artery aneurysms.
What are the clinical features of kawasaki disease? What are the diagnostic criteria?
The clinical features of KD reflect widespread inflammation of primarily medium-sized muscular arteries. Diagnosis is based upon evidence of systemic inflammation (eg, fever) in association with signs of mucocutaneous inflammation. The characteristic bilateral nonexudative conjunctivitis, erythema of the lips and oral mucosa, rash, extremity changes, and cervical lymphadenopathy typically develop after a brief nonspecific prodrome of respiratory or gastrointestinal symptoms. These characteristic clinical signs are the basis for the diagnostic criteria for KD
For each of the main presenting features of kawasaki disease, how often do they present in affected cases?
- Oral mucous membrane findings are seen in approximately 90 percent of cases of KD
- polymorphous rash in 70 to 90 percent
- extremity changes in 50 to 85 percent
- ocular changes in >75 percent
- cervical lymphadenopathy in 25 to 70 percent.
These findings are often not present at the same time, and there is no typical order of appearance.
Describe fever as a clinical manifestation of kawasaki disease?
- An elevated body temperature is the most consistent manifestation of KD.
- minimally responsive to antipyretic agents, and it typically remains above 38.5ºC (101.3ºF) during most of the illness. On the other hand, fever may be intermittent and may be missed by parents who use tympanic, temporal, axillary, or similar temperature measurement methods that are less reliable than oral or rectal methods. Thus, the diagnosis should be considered in all children with prolonged, unexplained fever ≥5 days but should still be considered in seemingly afebrile children who have other findings consistent with KD
Describe conjunctivitis as a clinical manifestation of kawasaki disease
- Bilateral nonexudative conjunctivitis is present in more than 90 percent of patients
- Predominant bulbar injection typically begins within days of the onset of fever, and the eyes often have a significant erythema, which characteristically spares the limbus.
- Frequently photophobic.
- anterior uveitis may develop in up to 70 percent of children with ocular findings; therefore, slit-lamp examination may be helpful in ambiguous cases. The presence of uveitis provides further evidence for the diagnosis of KD since it is more commonly seen in KD than in other diseases with similar presentations
Describe mucositis as a clinical manifestation of Kawasaki disease
- Mucositis often becomes evident as KD progresses
- Cracked, red lips and a “strawberry tongue” are characteristic. The latter is a result of sloughing of filiform papillae and denuding of the inflamed glossal tissue. The bumps on the “strawberry” are the remaining fungiform papillae.
- manifestations of oral mucositis may occur singly, in a very mild form, or not at all.
- Discrete oral lesions, such as vesicles or ulcers, and tonsillar exudate are suggestive of a disease process other than KD
Describe rash as a clinical manifestation of kawasaki disease?
- The cutaneous manifestations of KD are polymorphous.
- Rash usually begins during the first few days of illness, typically as perineal erythema and desquamation, followed by macular, morbilliform, or targetoid skin lesions of the trunk and extremities.
- Vesicular or bullous lesions generally are not observed, but KD may trigger a psoriasiform eruption in children not previously recognized to have psoriasis.
- Patients may also have redness or crust formation at the site of Bacille Calmette-Guérin (BCG) inoculation. This finding is more useful for increasing the level of suspicion for KD in countries where BCG vaccine is routinely given
Describe the extremity changes as a clinical manifestation of kawasaki disease?
- Changes of the extremities are generally the last manifestation to appear.
- Children develop an indurated edema of the dorsum of their hands and feet and a diffuse erythema of their palms and soles.
- The convalescent phase of KD is often characterized by sheet-like desquamation that begins in the periungual region of the hands and feet and by linear nail creases (Beau’s lines). The prevalence of periungual desquamation in patients with KD has been reported to vary from 68 to 98 percent
Describe lymphadenopathy as a clinical manifestation of kawasaki disease
- Cervical lymphadenopathy is the least consistent feature of KD, absent in as many as one-half to three-quarters of children with the disease.
- lymphadenopathy tends to primarily involve the anterior cervical nodes overlying the sternocleidomastoid muscles.
- Often, only a single, large node is palpable, although ultrasound imaging of the neck typically reveals numerous discrete nodes arranged like a bunch of grapes.
Diffuse lymphadenopathy or other signs of reticuloendothelial involvement (eg, splenomegaly) should prompt a search for alternative diagnoses
Describe cardiac findings as a clinical manifestation of kawasaki disease
- Cardiovascular findings are not part of the diagnostic criteria of KD, but they support the diagnosis since most conditions that mimic KD do not involve the heart.
- Cardiac manifestations during the first week to 10 days of illness may include tachycardia out of proportion to the degree of fever and gallop sounds.
- These physical exam findings are the result of lymphocytic myocarditis that is ubiquitous in children with KD. In addition, heart sounds may be muffled due to a pericardial effusion, which is detected in approximately 30 percent of children with KD. Such effusions are usually small; significant fluid collections and tamponade are rare.
With improved echocardiographic techniques and better understanding of age and sex norms for CA diameters, approximately 30 percent of patients with KD are found to have CA dilatation at diagnosis. Frank aneurysms are usually not seen until after day 10 of illness. Severely ill patients, particularly young infants, may develop fusiform aneurysms of other nonvisceral medium-sized arteries, most characteristically involving the brachial arteries. These are easily palpable or visible in the axillae, although they may be mistaken for enlarged lymph nodes. In addition, young infants may have cold, pale, or cyanotic digits of the hands and feet due to reduced perfusion. Gangrene may, in rare cases, cause loss of fingers or toes during this acute period.
Is arthritis a common feature of kawasaki disease? How often does it occur?
Arthritis is not included in the diagnostic criteria but has been reported in 7.5 to 25 percent of patients with KD
What are other nonspecific findings in kawasaki disease patients that commonly occur during the prodrome of the illness, 7-10 days before the typical mucocutaneous features develop?
●Diarrhea, vomiting, or abdominal pain – 61 percent
●Irritability – 50 percent (older children with KD more commonly present with lethargy than irritability)
●Vomiting alone – 44 percent
●Cough or rhinorrhea – 35 percent
●Decreased oral intake – 37 percent
●Joint pain – 15 percent
Patients with gastrointestinal involvement often have pseudo-obstruction on radiologic studies. The presentation of gastrointestinal symptoms before typical KD features may delay the diagnosis and lead to unnecessary invasive procedures including surgery.
Infants with kawasaki disease are at increased risk of…?
CA Aneurysms, possibly in part because of delay in treatment due to their lack of diagnostic criteria
Even in infants diagnosed and treated before the 10th day of illness, the incidence of CA abnormalities is significantly higher than it is in older patients
What are some laboratory findings which might support the diagnosis of kawasaki disease?
No laboratory studies are included among the diagnostic criteria for typical KD. However, certain findings may support the diagnosis of KD, particularly in incomplete cases:
●Systemic inflammation is characteristic of KD. Elevated ESR/CRP, thrombocytosis that generally develops after the seventh day of illness, leukocytosis, and a left-shift (increased immature neutrophils) in the white blood cell (WBC) count.
Treatment with intravenous immune globulin (IVIG) usually raises the ESR, so this lab test should not be measured after a child receives IVIG. On the other hand, control of inflammation by IVIG accelerates the decrease in CRP, making this a more useful marker of disease activity in a treated child.
Ferritin is another acute-phase reactant that is elevated in inflammatory conditions such as KD, usually less than five times the upper limit of normal.
Platelet counts generally rise by the second week of illness. In some studies, the degree of thrombocytosis correlates with the risk of coronary artery (CA) changes in KD.
Thrombocytopenia, high triglycerides, low sodium, elevated liver function tests, and monocytes/macrophages in cerebral spinal fluid (CSF) can all be signs of subclinical MAS and may warrant further diagnostic testing.
●Children with KD often present with a normocytic, normochromic anemia. Hemoglobin concentrations more than two standard deviations below the mean for age are noted in one-half of patients within the first two weeks of illness.
●Urinary microscopy commonly reveals WBCs. Pyuria is usually of urethral origin and therefore may be missed on urinalyses obtained by bladder tap or catheterization. The WBCs are not polymorphonuclear leukocytes and therefore are not detected by dipstick tests for leukocyte esterase. Thus, children with suspected KD should have a clean voided or bagged urine specimen collected for microscopic examination in order to detect this characteristic feature.
●Transaminitis can occur. In addition, a minority of children develop obstructive jaundice from hydrops of the gallbladder.
●CSF may display a mononuclear pleocytosis without hypoglycorrhachia (decreased CSF glucose) or elevation of CSF protein.
●Similarly, arthrocentesis of inflamed joints in KD typically demonstrates a pleocytosis, with 125,000 to 300,000 WBCs/mm3, primarily neutrophils.
●Children with KD develop significant perturbations in serum lipid profiles, including elevated triglycerides and low-density lipoproteins, and depressed high-density lipoproteins, as is often observed in a variety of infectious and inflammatory conditions. A return to normal generally occurs within weeks or months following IVIG therapy, though abnormalities may persist for years in children who are not treated with IVIG.
●Hyponatremia (serum sodium <135 mEq/L) may be seen and is associated with an increased risk of CA aneurysms.
