Kawasaki disease

• 1. Introduction

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  Kawasaki disease left its mark on a child's heart long before anyone gave it a name. The preserved heart of a seven-year-old boy who died in 1870 was examined many years later. It held three aneurysms in the coronary arteries, with clots inside them, and tissue changes that match this illness. The disease is also called mucocutaneous lymph node syndrome. It is rare and mostly strikes children under five. Its cause is still unknown. Yet in developed countries it is the leading cause of acquired heart disease in children. How does a fever that looks ordinary turn into a threat to the heart? Why do doctors struggle to recognize it? And why has decades of searching failed to reveal what sets it off?

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• 2. The Fever and the Rash

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  A temperature of 39 to 40 degrees Celsius, rising and falling but never quite leaving, is the opening act. Paracetamol and ibuprofen barely touch it, and antibiotics do nothing. The first day of fever counts as the first day of the illness. Left alone, the fever usually lasts one to two weeks, and sometimes three to four. Extreme irritability tends to follow.

  After the fever, the most common sign is red, inflamed eyes on both sides. The eyes produce no pus and usually do not hurt. The mouth changes too. Lips swell and crack vertically, and the tongue turns the bright red of a strawberry, with its small bumps standing out.

  In 50 to 75 percent of children, a lymph node in the neck swells. For diagnosis it must measure at least 15 millimeters across. Sometimes it is the first thing anyone notices, so a child with fever and a swollen neck who ignores antibiotics deserves a second look.

  The hands and feet tell their own story. Palms and soles turn sharply red, and the backs of the hands and feet swell painfully. Affected children often refuse to hold anything or put weight on their feet. Two to three weeks after the fever starts, skin begins to peel around the nails and can spread across the palms and soles. About 11 percent of children keep peeling for years.

  A rash usually covers the trunk and can reach the face and limbs. It does not itch, and it never forms blisters. One to two months in, deep grooves called Beau's lines may cross the nails, and nails are sometimes shed.

  The body-wide inflammation can reach almost anywhere. Doctors have recorded joint pain, diarrhea, vomiting, inflamed membranes around the brain, and even sensorineural deafness. One odd sign is redness and hardening at the scar where a child received a BCG vaccination.

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• 3. The Heart at Risk

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  Around the tenth day of illness, on average, an aneurysm in a coronary artery can first be detected. Among untreated children, 20 to 25 percent develop them. Doctors sort them by the width of the vessel. Small ones are under 5 millimeters, medium ones run from 5 to 8, and giant ones exceed 8. The peak for dilation comes within four weeks, and the saccular and fusiform shapes tend to form between day 18 and day 25.

  The illness moves through three phases. In the acute phase, lasting one to two weeks, the heart muscle is often inflamed, and fluid may gather around the heart. Aneurysms generally cannot yet be seen on ultrasound. In the subacute phase, which runs to about four weeks, they usually appear, and the risk of sudden death peaks. The convalescent stage ends once the blood's sedimentation rate returns to normal, usually after six to eight weeks.

  Treatment does not remove every danger. Even when children receive high-dose immunoglobulin within ten days, 5 percent still develop at least temporary dilation. One percent develop giant aneurysms. Death comes from a heart attack when a clot blocks an aneurysm, or from a large aneurysm rupturing. It is most common two to 12 weeks after onset.

  Several warning signs predict who is in danger. They include male sex, age under one year, a fever that persists after treatment, low hemoglobin, low albumin and high levels of C-reactive protein. Half of the affected vessels heal within one to two years. Healing itself can narrow the artery and starve the heart of oxygen.

  Children having a heart attack look different from adults. Shock, restlessness, vomiting and abdominal pain are the main signs, and chest pain mostly appears in older children. Most attacks happen during sleep or rest, and about a third produce no symptoms at all. The first year carries the highest risk.

  Valves can leak during the acute phase, usually temporarily. A few cases worsen, and some need valve replacement. Giant aneurysms bring the worst outlook and may call for angioplasty, stenting, bypass surgery or even a heart transplant. Many heart attacks in young adults have since been traced back to Kawasaki disease that went unrecognized in childhood. Aneurysms from the illness are believed to account for 5 percent of acute coronary syndrome in adults under 40.

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• 4. Hunting the Trigger

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  Winds blowing out of central Asia seem to track the arrival of new cases in Japan, Hawaii and San Diego. Researchers have linked seasonal waves of the disease to wind patterns high in the atmosphere. These patterns are in turn shaped by El Niño events in the tropical eastern Pacific. The idea is that something airborne, inhaled by a susceptible child, sets off the immune response. Scientists flew air filters at altitude above Japan to look for a pathogen. One suggested origin lies in northeastern China.

  The circumstantial case for an infection is strong. Recurrences are unusual, which suggests a single pathogen rather than many different viruses or bacteria. Some have proposed a novel RNA virus entering through the airways. Yet despite intensive effort, no single germ has been identified. For a time, researchers debated whether a superantigen, a trigger known for extreme immune activation, was responsible. Current thinking favors an overreaction to an ordinary antigen, the kind that normally leaves lasting protection.

  Genes matter as well. Children of Japanese descent have higher rates around the world, and relatives of patients are more often affected. Variants in genes including FCGR2A, CASP3, BLK, ITPKC, CD40 and ORAI1 have been tied to susceptibility, outcome and aneurysm risk. Most of these genes regulate the immune system. Altered DNA methylation has also been proposed as an early step during the acute phase.

  Even the disease's category is contested. Some call it a response to an infection, some an autoimmune process, and some an autoinflammatory disease involving the innate immune system. It counts as a necrotizing vasculitis of medium-sized vessels, and it lacks the antibodies seen in related disorders such as granulomatosis with polyangiitis. That absence matters for choosing treatment.

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• 5. Diagnosis by Elimination

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  No blood test can confirm Kawasaki disease. The classic rule asks for five days of fever plus four of five changes. These are red eyes, changes in the lips or mouth, swelling or redness of the hands and feet, a rash on the trunk, and a neck lymph node of at least 15 millimeters. Many children, especially infants, never display the full set. Many experts now advise treating after only three days of fever when three features are present. Finding coronary aneurysms on ultrasound can settle the matter on its own.

  The list of lookalikes is long. Scarlet fever, toxic shock syndrome, juvenile idiopathic arthritis, measles, Lyme disease and childhood mercury poisoning all appear on it. Because of this, children are often not diagnosed until they have seen several health-care providers.

  Supporting tests build the picture. Blood work may show anemia, a high platelet count and raised inflammation markers. Ultrasound of the heart can reveal subtle changes in the arteries. Angiography remains the gold standard for spotting aneurysms but is rarely needed today. A biopsy is almost never performed.

  In 2020, reports surfaced in the United States and Europe of a Kawasaki-like illness after exposure to the coronavirus SARS-CoV-2. Britain's Royal College of Paediatrics and Child Health called it paediatric multisystem inflammatory syndrome. The Centers for Disease Control and Prevention named it multisystem inflammatory syndrome in children. Its features appear distinct from Kawasaki disease. A similar condition in adults has been labeled MIS-A.

  True Kawasaki disease in adults is rare. Adults more often have neck lymph node swelling, hepatitis and joint pain than children do.

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• 6. Treatment and Its Puzzles

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  Immunoglobulin given through a vein is the standard first treatment, and fever often breaks within 24 hours. Timing matters. It works best in the first seven days of fever and still lowers the risk of coronary damage when given within ten. If the fever persists, a second dose can follow, and rarely a third.

  Aspirin is the odd partner in the regimen. Doctors give it at high doses until the fever subsides, then at a low dose, usually for about two months, to stop clots forming. Aspirin is normally avoided in children because it is linked to Reye syndrome. For that reason, children on long courses must be vaccinated against chickenpox and influenza. Aspirin alone is less effective than immunoglobulin, and some question its value.

  About 15 to 20 percent of children show a fever that persists or returns after the first infusion. These cases are classed as resistant. In the largest study of resistant disease so far, infliximab worked faster and more safely than a second immunoglobulin dose. A 2019 study found that adding ciclosporin helped suppress coronary abnormalities.

  Corticosteroids are contested. One randomized trial found no benefit from adding them, and they have been linked to a higher aneurysm risk, so many consider them inadvisable. Yet a Cochrane review published in 2017 and updated in 2022 found improved coronary outcomes in children. Patients in Asia and those with higher risk scores may gain most.

  The stakes of treatment are clear in the death rates. Without it, about 1 percent of children die. With it, the figure falls to 0.17 percent. Across all patients, roughly 2 percent die of coronary complications. Children who develop aneurysms need lifelong monitoring by specialized cardiology teams.

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• 7. Counting the Cases

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  In Japan, the most recent study put the attack rate at 218.6 per 100,000 children under five, about one in 450. At that pace, more than one in 150 Japanese children will develop the disease during their lifetimes. Elsewhere the range runs from 8 to 67 per 100,000 under-fives. Boys are affected more often than girls, and people of Asian ancestry bear the greatest burden.

  In the United States, between 2,000 and 4,000 cases are identified each year, or 9 to 19 per 100,000 children under five. Winter and early spring bring the most cases in the continental United States. Boys outnumber girls by roughly 1.5 to 1.7 to one. Overall, 80 percent of patients are younger than five.

  Britain tells a story of steady growth. Before 2000, fewer than one in 25,000 people per year was diagnosed. In 1991 there were four cases per 100,000 children, and by 2000 there were eight. By 2017 the figure had reached 12 per 100,000, with 419 diagnosed cases in the United Kingdom.

  Kawasaki disease is now the most commonly diagnosed vasculitis in children worldwide. In the United States and other developed nations, it appears to have displaced acute rheumatic fever as the most common source of acquired childhood heart disease.

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• 8. A Tokyo Pediatrician's Discovery

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  In January 1961, a four-year-old child with a fever and a rash came to the Red Cross Hospital in Tokyo. The pediatrician who examined the child, Tomisaku Kawasaki, was struck by the pattern. He later published a report on 50 similar cases. Further study convinced him and his colleagues that the heart was involved. Of 23 cases they examined, 11 patients, or 48 percent, had abnormal electrocardiograms.

  The wider world learned of it slowly. The first description in English-language medical literature appeared in 1974. In 1976, Melish and colleagues described the same illness in 16 children in Hawaii. Working separately, Melish and Kawasaki had arrived at the same diagnostic criteria.

  Why cases began turning up on every continent around the 1960s and 1970s is unclear. Doctors may have mistaken it for scarlet fever. Easier recognition in modern health care, including the widespread use of antibiotics, may also have helped. Old Western pathology reports of infantile polyarteritis nodosa match the fatal cases now attributed to Kawasaki disease.

  Those two independently built sets of criteria are still the basis for diagnosing the classic form of the illness today.

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