New Treatment Lessens Threat of Kawasaki Syndrome
by Amy Roffmann New

Toddlers with fevers? Only about as common as sand on the beach. But for       
toddlers with Kawasaki syndrome, fever is just one of the early signs of a     
very serious illness.

Kawasaki disease, or Kawasaki syndrome, is an infectious inflammatory disease  
that affects mainly infants and young children. At first, the                  
symptoms--fever, rash, watery eyes, swollen lymph nodes--look like those seen  
with many of the bugs kids pick up all the time. 

But this is no simple bug. It affects many systems in youngsters' bodies, but  
damage to the heart and surrounding tissue is of the greatest concern. Left    
untreated, Kawasaki syndrome can damage the coronary arteries that feed the    
heart, possibly causing a massive heart attack. Recently, the Food and Drug    
Administration approved use of a previously licensed biologic, intravenous     
immune globulin--Immune Globulin Intravenous (Human)--to help minimize the     
complications of Kawasaki syndrome.

Although there have been rare reports of Kawasaki syndrome in adults, the      
disease primarily affects children under 5 years old, with most cases          
affecting 1- to 2-year-olds. The disease affects boys about 50 percent more    
often than girls, and seems to affect children of Asian descent at a much      
higher rate than children of African or European descent. "The typical         
patient would be a 2-year-old boy with high fever," says Stanford Shulman,     
M.D., Chief of Infectious Diseases at Children's Memorial Hospital in Chicago.

There have been three epidemics of the disease in Japan: in 1979, 1982 and     
1986. According to surveys of those epidemics, 1 in 250 Japanese children      
with the disease died from it, and 15 to 20 percent developed heart            
aneurysms. These abnormal enlargements of blood vessels cause a weakening of   
the vessel that could burst at any time, threatening the patient's life.

Kawasaki syndrome is not considered contagious, although outbreaks tend to     
occur in certain geographic regions. The disease is most common in Asia,       
particularly in Japan and Korea. In the United States, the incidence in        
children of Japanese or Korean background is four times greater than in        
children of European background. This link puzzles researchers. The disease    
is more prevalent even in Asian children with little or no exposure to the     
foods or customs of Asian culture. 

In Hawaii, the disease is far more common among Japanese-American children.    
While Japanese-Americans compose one-third of Hawaii's population,             
Japanese-American children account for 85 to 90 percent of the cases of        
Kawasaki syndrome in that state. Most of these children are third- or          
fourth-generation Americans with little or no Japanese cultural influence in   
their daily lives. These statistics appear to indicate a genetic factor that   
researchers are not yet able to explain.

The disease was first described by Tomisaku Kawasaki, M.D., a Tokyo            
pediatrician, in 1967, but wasn't reported in English literature until 1974.   
Fever develops within the first few days of onset of the disease. Many         
Kawasaki patients experience abrupt spikes in temperature--several spikes a    
day for five or more days--as the disease begins. Left untreated, the spiking  
can continue for as long as four weeks.

A measles-like rash usually accompanies the fever, and lymph nodes in the      
neck swell. Conjunctivitis, characterized by red eyes and swollen eyelids,     
may also develop in the first few days. The lips, tongue and throat may        
become red and swollen. One of the most distinguishing symptoms of Kawasaki    
disease is the redness and swelling of palms and soles within a few days of    
onset. After a couple of weeks, the skin of the hands and feet begins to peel.

Diagnosis Critical

Early and accurate diagnosis is critical to successful treatment, as the       
disease can start to damage the heart after just one week of illness.

But diagnosis is difficult. One problem is that the symptoms don't always      
appear together. Some patients experience all of the symptoms, and some have   
only a few. Infants are less likely than toddlers to have all symptoms.

Fever and swollen glands are a source of concern for any parent, but "cardiac  
involvement is the only long-term issue in Kawasaki disease," says Shulman,    
"It's the only thing of real importance."

The acute phase of Kawasaki syndrome is followed by a convalescent stage,      
which can be misleading. Often patients' families see improvement, even        
without treatment. Fever is reduced--sometimes temperature even returns to     
normal--skin redness subsides, and skin begins to peel.

"The worrisome thing [during this stage]," says Shulman, "is that in those     
children who are destined to develop heart involvement, this is the period of  
time it begins to show up."

According to a study by the Division of Pediatric Cardiology of Columbia       
University's College of Physicians and Surgeons, 25 percent of Kawasaki        
patients show some signs of heart inflammation--such as fast or irregular      
heartbeat--during this stage. Heart inflammation is a warning sign indicating  
the possibility of damage to the cardiovascular system. Although heart         
inflammation may subside over time, aneurysms, permanent and sometimes         
life-threatening dilations of blood vessels, may occur.

"The peak size of an aneurysm is typically reached three to four weeks after   
the onset of fever," says Jane Newburger, M.D., a pediatric cardiologist with  
Children's Hospital in Boston. This makes it important to monitor Kawasaki     
patients carefully. Once an aneurysm has formed, there is no guarantee that    
the damage can be reversed. However, treatment is aimed at preventing the      
formation of aneurysms.

The damage from Kawasaki disease is thought to start with an inappropriate     
immune response. Children with the disease produce an unusually large number   
of immune cells. The immune cells go haywire and begin to attack artery        
walls.  

Once the artery wall is damaged, it becomes a dam where platelets can form a   
blood clot. This clot, combined with the damage to the artery wall, further    
enlarges the artery, causing an aneurysm. Once this happens, blood flow is     
severely restricted, and a heart attack is possible. (See "Aneurysms           
Difficult to Diagnose, Complex to Cure" in the October 1992 FDA Consumer.)

Aspirin and IGIV

Early diagnosis and treatment helps minimize the danger from Kawasaki          
syndrome. Although the cause is unknown, it can be treated effectively, says   
Mary Glode, M.D., an infectious disease specialist with the Department of      
Pediatrics of the University of Colorado in Denver.

Researchers have found that a combination of aspirin and intravenous immune    
globulin (often abbreviated IGIV) is highly effective in preventing long-term  
coronary artery problems from Kawasaki syndrome. Initially, patients were      
given aspirin alone, but the findings of researchers prompted FDA to recently  
approve the addition of IGIV to the treatment of Kawasaki patients. 

The role of IGIV is unclear. IGIV is a product made by purifying the           
naturally occurring antibodies in human blood plasma. Several pharmaceutical   
companies produce IGIV, but only one product, produced by Oesterreichisches    
Institut fuer Haemoderizate (OIH), a pharmaceutical company based in Austria,  
has been approved by FDA for use in treatment of Kawasaki disease.

According to John Finlayson, Ph.D., a protein specialist with FDA, "We don't   
really understand why immune globulin works, but the major benefit is in       
minimizing coronary aneurysms."

The immune globulin is given intravenously in either a single large dose of 2  
grams per kilogram of body weight over 12 hours, or four smaller daily doses   
of 400 milligrams per kilogram (1 kilogram is about 2.2 pounds).

Besides minimizing the potential for cardiac damage, this treatment regimen    
seems to work to "turn off" the disease.  If treatment starts within 24 hours  
of the onset of the disease, the child is usually feeling much better by the   
next day.

According to Newburger, aspirin provides both an anti-inflammatory and         
anti-platelet effect. The anti-inflammatory effect keeps the arteries from     
swelling, and the anti-platelet effect prevents clots from forming in          
arteries. 

Aspirin is given is fairly high daily doses--from 30 to 180 milligrams per     
kilogram (for example, 405 to 2,430 milligrams per day for a 30-pound child)   
of the patient's body weight--for the first two weeks of the disease. (For     
comparison, one regular aspirin is 325 milligrams.) The dose is then lowered   
to 3 to 5 milligrams per kilogram for an additional six to eight weeks.

Patients who have some heart damage may be given low doses of aspirin for      
several months; those with more severe damage, for years.

Aspirin use in the treatment regimen for children is somewhat controversial.   
The association between aspirin and Reye syndrome in children with flu and     
chickenpox has made parents and doctors wary of using aspirin to treat         
children with any acute illness. 

However, no association has been reported between Reye syndrome and the use    
of aspirin in children with Kawasaki syndrome. Therefore, the benefits of its  
use in this instance, under a doctor's direction, outweigh its risks.          
Children who need to continue low doses of aspirin for long periods after the  
acute stage of the disease are monitored closely for signs of chickenpox or    
flu, and the aspirin can be stopped for a few days if a child develops         
symptoms of these illnesses.

Inexplicably, a possible connection has been made by some studies between      
children contracting Kawasaki syndrome and recently cleaned carpets.           
Researchers at Cornell University Medical Center were the first to find the    
apparent association in a survey of the families of Kawasaki patients and a    
separate control group. 

Researchers asked questions about other family members with the disease, the   
type of foods the patient had been eating, and whether or not the child was    
breast-fed.

The only factor that clearly differed between the two groups is that children  
with Kawasaki disease were more likely to have been exposed to carpets and     
rugs that had been shampooed, beaten, or vigorously cleaned within a month of  
the onset of illness. Most cases of Kawasaki syndrome occur between December   
and May, prompting some experts to recommend that families with infants and    
toddlers not clean carpets during winter and early spring.

Since the Cornell study, 13 additional studies have tested the connection.     
"Four studies have found an association between exposure to shampooed carpets  
and development of Kawasaki," says Shulman. "Nine of the studies failed to     
find an association."

Shulman explains that while the association is generally unproved, it may be   
valid in certain geographic locations. To be on the safe side, he recommends   
keeping children away from just-shampooed carpets for 24 to 48 hours.

Long-Term Outlook

According to Newburger, a Kawasaki patient's long-term outlook depends on how  
much damage is done to the heart. Patients who receive treatment early will    
likely suffer no damage to the arteries. More than half the children who do    
develop aneurysms recover within a year.

Patients who don't fare as well are those who don't receive treatment and      
develop extremely large aneurysms. "The most [severely affected]               
patients--those with aneurysms of at least 8 millimeters--those patients will  
probably not return to normal," says Newburger.

Because the disease was so recently identified, doctors don't yet know if      
there are any long-term effects that aren't apparent when the acute phase of   
the disease ends.

While most childhood fevers, sniffles, and watery eyes are no reason for       
alarm, parents should be aware that accompanied by other symptoms, the         
illness may require immediate medical attention. Recognized and treated        
early, Kawasaki syndrome can be stopped before it becomes a life-threatening   
problem.

Amy Roffman New is a writer in Chandler, Ariz.