THE ETIOLOGY OF KAWASAKI DISEASE:
A COMMON MANIFESTATION OF AN UNCOMMON AGENT, OR AN UNCOMMON MANIFESTATION OF A COMMON AGENT?
THOMAS J. A. LEHMAN, MD
CHIEF, DIVISION OF PEDIATRIC RHEUMATOLOGY
THE HOSPITAL FOR SPECIAL SURGERY, AND
ASSOCIATE PROFESSOR OF PEDIATRICS,
CORNELL UNIVERSITY MEDICAL CENTER
535 E. 70TH ST
NEW YORK, NY 10021
The etiology of Kawasaki disease remains elusive. As illustrated by manuscripts in this and previous collections, attempts to demonstrate a viral or rare bacterial etiology have been unsuccessful. Much emphasis has been placed on the need to utilize new technologies with polymerase chain reaction and molecular approaches in our search. These techniques may yet lead to the etiology of Kawasaki disease. However, the indiscriminate application of increasingly complex and expensive technology ignores both the available epidemiological data and the lessons learned from similar illness in both human an animal models.
Kawasaki disease preferentially affects young children. The peak incidence and most severe effects occur in the first two years of life with a rapid decline thereafter. It affects boys more often than girls, and it affects Asians more often than Caucasians. There is a fairly constant rate of endemic disease upon which periodic epidemics are superimposed. The epidemic occurrence of this disease has focused attention on an infectious agent. But, the attack rate in siblings and family members is only two percent. Simple exposure to an infectious agent is clearly insufficient.
Since adults and siblings are highly protected from Kawasaki disease, the special vulnerability of young children must play an important role in susceptibility. Is Kawasaki disease due to an unusual agent to which only young children are susceptible? It is far more likely that Kawasaki disease is due to a common agent to which adults and most older children have successfully developed immunity without evident disease manifestations.
Acute rheumatic fever and paralytic polio are examples of illness caused by widespread agents which have disastrous consequences for a small number of exposed individuals while leaving the majority unharmed. In neither case was the responsible agent detected by culture of the responsible organism from affected individuals. Even with the most sophisticated techniques available and knowledge of the offending organism it is not possible to obtain streptococcal antigens from the heart of individuals affected with rheumatic fever.
The special vulnerability of children in the earliest years of life is best illustrated by infantile botulism. It was the association of this illness with exposure to honey and the finding of botulinum spores in the honey that led to discovery of its etiology. Rug shampooing, proximity to water, and flooding are clues given to us by the epidemiologists for Kawasaki disease. All suggest an association with dampness. The proper interpretation of this data remains unclear. Perhaps because we do not know the proper questions to ask.
Potential hints are available from the animal data. Cell wall materials from Lactobacillus casei, L. acidophillus, L. sake, and Streptococcus pyogenes have all been demonstrated to cause coronary arteritis in mice. Although mice are generally susceptible, genetic control of susceptibility to bacterial cell wall-induced diseases is clearly evident in inbred rats. Each of the above bacteria will induce polyarthritis in rats. Not all inbred rat strains are susceptible, but the pattern of strain susceptibility is the same for all of the bacteria. The development of arthritis in the rats and coronary arteritis in mice are not unique manifestations of a single infectious agent, instead they are manifestations of a genetically determined pathologic 'final common pathway' occurring in response to several different agents. Reiter's syndrome in which a variety of intestinal or genital infections are followed by the triad of arthritis, urethritis, and conjunctivitis is a direct human parallel to this situation.
Does this animal model have relevance to the etiology of Kawasaki disease? The latobacilli which are capable of inducing disease in this animal model are widespread bacteria, commonly associated with water and foodstuffs (especially fermented foods) which are uniquely capable of tolerating an acidic environment. All of us are colonized by these agents when food stuffs are introduced during the first few years of life. A renewed and more intensive investigation of food stuffs and feeding patterns might provide information which could explain the endemic background level of disease among susceptible individuals. Epidemic disease might be explained by flooding (since standing bodies of water normally contain lactobacilli), contamination of a food source, or a viral infection which induces susceptibility to the offending agent.
It is clearly possible that none of the data from animal models is applicable to Kawasaki disease. However, it is important that we carefully analyze what is known about this and similar diseases for which determination of the etiologic agent has been difficult before assuming that ever more expensive technology will provide the answer.