Kawasaki disease (KD) is the archetypal pediatric vasculitis, exemplifying the unique aspects and challenges of vascular inflammation in children. The condition is almost unheard of in adults, is closely associated with infections, and is self-limited, with fever resolving after an average of 12 days even without treatment. Yet KD is also a potentially fatal disease and the most common cause of acquired heart disease in the developed world. Unraveling of the developmental, immunologic, and genetic secrets of Kawasaki disease promises to improve our understanding of vasculitis in particular, and perhaps also to provide a window on the fundamental mysteries of inflammatory diseases in general.
Key points
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Many of the differences between adult and pediatric vasculitis are highlighted in Kawasaki disease, a relatively common condition in children yet essentially unknown in adults.
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Kawasaki disease is an acute, self-limited vasculitis that affects 0.01% of children during or shortly after one of many common viral and bacterial infections.
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Therapy with IVIG within 10 days of onset effectively controls the signs and symptoms of mucocutaneous inflammation and cervical lymphadenopathy characteristic of KD.
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Coronary artery inflammation with aneurysm formation is the major morbidity associated with KD; it may lead to death in >1% of untreated cases.
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IVIG prevents aneurysms more than 95% of the time, though identifying those most at risk and effectively treating resistant cases remains a challenge.
Introduction
Vasculitis means something different to a pediatrician than it does to an internist. In children, the most common forms of vasculitis, Henoch-Schönlein purpura (HSP) and Kawasaki disease (KD), have a combined incidence of almost 1/4000 ( Table 1 ). These are conditions that are typically cared for by generalists, and in most cases, they resolve completely and without sequelae, if clearly delineated guidelines are followed.
| Feature | HSP | PAN | KD |
|---|---|---|---|
| Gender/Incidence | 66% male 13.5/100,000 | 50% male 1/100,000 | 65% male 10/100,000 |
| Trigger | 33% streptococcal | 30% streptococcal | ∼ 40% evidence of an infection |
| Genetic modifiers | MEFV, IgA | MEFV | CCR5, IL-4 |
| Outcome | 1% renal failure | 50% systemic vasculitis | 20% coronary artery lesions |
| Therapy | Support, steroids | Steroids, cytotoxics | 95% IVIG, ∼5% salvage |
The types of pediatric vasculitis that reach a rheumatologist are different. Whether the condition involves small, medium, or large vessels, these forms of vasculitis tend to be progressive and life threatening. They are largely incurable, and therefore are likely to affect pediatric patients for decades. As a result, even minor errors in treatment can lead to a widening ripple of damage and disability, which affect the rest of the child’s life.
Bridging this chasm between the common and the rare is a major challenge for all clinicians, but perhaps most dramatic in the case of pediatric vasculitides. Thus, in this article various types of vascular inflammation in children are discussed: primary and secondary, self-limited and chronic, acutely life threatening and spontaneously remitting. The major focus is on key points in the natural history of the conditions at which interventions can be most effective.
Introduction
Vasculitis means something different to a pediatrician than it does to an internist. In children, the most common forms of vasculitis, Henoch-Schönlein purpura (HSP) and Kawasaki disease (KD), have a combined incidence of almost 1/4000 ( Table 1 ). These are conditions that are typically cared for by generalists, and in most cases, they resolve completely and without sequelae, if clearly delineated guidelines are followed.
| Feature | HSP | PAN | KD |
|---|---|---|---|
| Gender/Incidence | 66% male 13.5/100,000 | 50% male 1/100,000 | 65% male 10/100,000 |
| Trigger | 33% streptococcal | 30% streptococcal | ∼ 40% evidence of an infection |
| Genetic modifiers | MEFV, IgA | MEFV | CCR5, IL-4 |
| Outcome | 1% renal failure | 50% systemic vasculitis | 20% coronary artery lesions |
| Therapy | Support, steroids | Steroids, cytotoxics | 95% IVIG, ∼5% salvage |
The types of pediatric vasculitis that reach a rheumatologist are different. Whether the condition involves small, medium, or large vessels, these forms of vasculitis tend to be progressive and life threatening. They are largely incurable, and therefore are likely to affect pediatric patients for decades. As a result, even minor errors in treatment can lead to a widening ripple of damage and disability, which affect the rest of the child’s life.
Bridging this chasm between the common and the rare is a major challenge for all clinicians, but perhaps most dramatic in the case of pediatric vasculitides. Thus, in this article various types of vascular inflammation in children are discussed: primary and secondary, self-limited and chronic, acutely life threatening and spontaneously remitting. The major focus is on key points in the natural history of the conditions at which interventions can be most effective.
Epidemiology
Vasculitis is rare in children. Its incidence is between 10 and 50/100,000 in various studies and populations, although all such estimates are affected by referral patterns and selection bias. Vasculitis generally makes up less than 5% of referrals to pediatric rheumatologists, whereas if the 2 most common types, KD and HSP, are removed, they represent less than 1% of chronic inflammatory disorders of childhood.
The epidemiology of vasculitis in children sheds some light on their possible pathogenesis and in particular suggests a close connection with transmissible agents. About one-third of cases of HSP and of cutaneous polyarteritis nodosa (PAN) occur after a streptococcal infection, whereas cases of isolated angiitis of the central nervous system (CNS) often follow a viral illness. A similar percentage of children with KD have evidence of an infection, although in this condition, it is concurrent with the acute manifestations of the vasculitis and may be bacterial or viral, systemic or focal. Further supporting the theory that many pediatric vasculitides are triggered by transmissible agents is the fact that boys are 50% more likely than girls to develop HSP, KD, granulomatosis with polyangiitis, and PAN. The 2 most common adult vasculitides, on the other hand, giant cell arteritis and temporal arteritis, occur predominantly in women. At all ages, women’s immune systems have a higher set point than men, making them more susceptible to diseases of overactive immunity and less susceptible to infections.
Further epidemiologic evidence that KD is etiologically related to infections includes the fact that the average age of children with KD is about 2 years, and occurrence beyond late childhood is rare. This finding suggests that the trigger is an agent or agents to which most people are exposed and become immune by late childhood. Epidemics occurred regularly in the 1980s, and during these outbreaks, the average age of patients decreased, whereas the percentage of girls increased, again typical of infections. Nonetheless, decades of attempts to prove that certain viruses (eg, Epstein-Barr virus [EBV], parvovirus, human immunodeficiency virus 2), bacterial toxins (eg, streptococcal erythrogenic toxin, staphylococcal toxic shock toxin), or specific pathogens account for most cases have not been substantiated. With each failure to confirm a putative agent as the cause of KD, and in view of the similarity between KD and known reactive vasculitides such as HSP and acute rheumatic fever, the greater the likelihood that KD represents a final common pathway of immune-mediated vascular inflammation after a variety of inciting infections.
Risk factors
Because the causes of most types of vasculitis are not known, it is not surprising that risk factors for their development are equally hidden. As noted earlier, a sizable number of cases of pediatric vasculitis follow infections or immunizations, but the overall percentage of children who develop vasculitis after exposure to these agents is vanishingly small. Genetic factors offer an attractive explanation for individual susceptibility, but even the many immunomodulatory, haplotypic, and vascular genes associated with specific vasculitides do not explain the phenomenon. Even in KD, the most thoroughly analyzed pediatric vasculitis, the relative risk conferred by polymorphisms represents only a small percentage of the overall risk of contracting the disease. Only in rare cases of monogenic diseases, such as the recently identified vasculopathy associated with mutations in adenosine deaminase 2, can genetic factors reliably predict development of vasculitis. It seems that in most cases, interactions between numerous stochastic events are more important than effects of single genes, and although techniques for evaluating these factors are evolving rapidly, they are inadequate to pinpoint the cause of KD.
Pathophysiology
Despite extensive research, mechanisms underlying the onset and perpetuation of vascular inflammation are poorly understood. Some aspects of the development of KD are apparently unique, whereas others likely represent stereotypical expressions of disease limited by the anatomic, physiologic, and genetic characteristics of human beings. Epidemiologic and basic studies, animal models, and response to specific biological response modifiers are shedding light on the processes involved, in particular highlighting the following.
Pathologic Characteristics
The primary target of inflammation in KD is medium-sized muscular arteries. Although a variety of nonparenchymal vessels are involved, the coronary arteries are the most severely affected, and the most likely to suffer chronic damage. Early in the process, neutrophils invade the vessel walls, and a neutrophilic infiltrate is evident in the arterial wall of fatalities that occur within the first 2 weeks of disease. This process is followed by eosinophils and T cells (particularly CD8 T cells), confirmed by the presence of CD8 T cells in the arterial wall of fatalities that occur more than 2 weeks after disease onset.
Immunologic Response
Gene expression studies using DNA microarrays from acute-phase KD peripheral whole blood confirmed the increased relative abundance of transcripts associated with neutrophils and acute inflammation, including adrenomedullin, grancalcin, and granulin, and decreased abundance of transcripts associated with natural killer cells and CD8+ lymphocytes. In addition, the later phase of inflammation involves plasma cells (particularly IgA-producing), or macrophages, a pattern that is unique to KD. Together, these findings suggest a process initiated by an innate immune response, subsequently involving a response mediated by the acquired immune system. The combination leads to rapid destruction of luminal endothelial cells, elastic lamina, and medial smooth muscle cells, with resulting loss of structural integrity, arterial wall dilatation, and aneurysm formation.
Genetic Factors
Multiple facts support a significant genetic contribution to the development of KD, mitigated by environmental factors. The incidence of the disease is significantly higher in Asian populations, lower in white populations, and intermediate among Asian families living in the United States. In one Japanese study, concordance for KD was 13.3% in dizygotic twins and 14.1% in monozygotic twins, and the disease often involves succeeding generations within a single Japanese family.
Many studies using differing approaches to identify candidate susceptibility loci have identified a variety of genes associated with the risk of developing KD or the severity of the disease. These genetic hotspots include histocompatibility loci as well as genes involved in vascular homeostasis and immunoregulation. No single gene explains more than 1% of a patient’s risk of developing KD, so an understanding of interactions between polymorphisms is likely to be necessary before the implications of these genetic studies become evident.
Local Factors
Although coronary artery dilatation and aneurysm formation may occur in a variety of infectious (EBV), inflammatory (systemic lupus erythematosus) and vasculitic diseases (PAN), the specificity of this targeting is unique to KD. In general the characteristic predilection of different vasculitides for different anatomic sites remains unexplained, although it seems to depend on a variety of factors, including specificity of the triggering antigen, regional variations in cell surface receptors, and unidentified contributions of surrounding tissues. This remains a tantalizing hint to the pathogenesis of KD, but one which has yet to even be formulated as a question that may be investigated.
Clinical features
The clinical evolution of KD differs from that of other, more chronic vasculitides. Characteristic of any type of vasculitis, early findings are nonspecific, primarily reflecting systemic inflammation (fever, malaise, fatigue, failure to thrive, increased levels of acute-phase reactants). However, unique to KD, progression mimics an infectious disease, with development of a rash, mucosal inflammation and extremity changes. In the early 1960s, when Tomasaku Kawasaki attempted to convince his colleagues that mucocutaneous lymph node syndrome was a unique entity, he had to distinguish it from viral exanthema and Stevens-Johnson syndrome. The diagnostic criteria he established from clinical observation alone were able to identify a novel condition, and these same criteria continue to form the basis of diagnosing Dr Kawasaki’s eponymous syndrome ( Box 1 ).
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