A Disease Scattered to the 4 Winds

In 2013, a mother arrived at a Texas clinic with her 4-year-old son in tow. Three weeks earlier, he had been diagnosed with ringworm and given an antifungal (griseofulvin), but he had recently stopped eating. Concerned about his loss of appetite, she patiently waited for a doctor to see her son. When the doctor finally saw them, she informed him that it had been 2 days since her son ate. He also had begun to develop a rash on his face, trunk, and extremities and had some nasal congestion and an occasional cough. The doctor conducted a physical exam on the boy but there was nothing extraordinary other than his presenting symptoms: a “sand paper–like” erythematous rash and reddish mucosal tissue in his mouth and throat. He wasn’t feverish, his cough was not persistent, and a rapid strep test was negative. Believing he had contracted a virus, the doctor sent him home to rest.

After 2 days, the boy’s hands and feet began to swell and his mother returned to the clinic looking for answers. The erythema in his mouth and throat was more pronounced, the rash had not improved, and now his lips were peeling. He still was not feverish but his mother reported that he felt warm and that he experienced chills at night. Another physical exam was ordered and once again proved unremarkable. A pediatric infectious disease specialist was consulted and the boy was admitted to the hospital for further tests.

The tests indicated he had elevated levels of gamma-glutamyl transferase (GGT) and C-reactive protein (CRP), and an increased erythrocyte sedimentation rate (ESR). However, strep and throat cultures were negative, as was a urine culture. Both the urine Gram stain and ketones were within normal limits and he was alert and responsive. His symptoms were attributed to an allergic reaction of unknown etiology and he was sent home again. His mother was instructed to discontinue using the antifungal and to give him a regimen of Benadryl and Zantac.

Once again, after a few days, they returned to the clinic. She informed them that he had a slight temperature at night (99.5°F) and his rash was not improving. The skin around his fingers, toes, and perianal area had also begun to peel. This time, the physical exam revealed erythematous oral mucosa with the presence of a “strawberry tongue.” A slight but not clinically significant systolic murmur in the left lower intercostal space was noted and desquamation around the finger nails, toes, and perianal and groin regions was recorded. His hands and feet were still swollen and he was referred to an infectious disease clinic for tests.

His platelet levels were slightly elevated (466,000/mm3). However, the more concerning results were the consistently elevated levels of ESR (80 mm/hr), GGT (43 U/L), and CRP (3.8 mg/dL). After receiving serum results, they ran an electrocardiogram but his ST-T wave activity was normal. An echocardiogram revealed a mild tricuspid valve insufficiency but without any coronary artery ectasia, perivascular brightness, or aneurysm. His cervical lymph nodes showed no signs of inflammation and he had clear conjunctiva. He tested negative for influenza, respiratory syncytial, or adenovirus but tested positive for either rhinovirus or enterovirus. Based on these findings and his family history (the fact that his younger brother was diagnosed with Kawasaki disease [KD]), the pediatric infectious disease and cardiology consultants determined he had atypical or incomplete KD. He was readmitted to the hospital, where he received intravenous immunoglobulin and aspirin therapy.

The diagnostic criteria for KD include a high fever that is unresponsive to antibiotics and is present for at least 5 days, with 4 out of 5 accompanying symptoms:

1. Bilaterial conjunctival injection
2. Erythema of the oral mucosa: injected pharynx, injected and fissured lips, strawberry tongue
3. Peripheral edema, peripheral erythema, periungual desquamation
4. Polymorphous skin rash
5. Cervical lymphadenopathy

From the time of the first visit to the clinic, doctors were aware of his brother’s diagnosis. The chance of contracting the disease when one sibling is infected is associated with a 10-fold increased susceptibility compared with the general population. In fact, after his second visit, the specialist wanted to rule out the possibility of KD and admitted him to the hospital for tests. However, labs cannot confirm the disease, and because he never developed a fever, a key diagnostic requirement, the diagnosis took 10 days from the onset of symptoms.

Kawasaki Disease

Tomisaku Kawasaki, MD, for whom the disease is named, first published a detailed report describing the disease in 1967. And since 1970, Japan has conducted nationwide surveys every 2 years, tracking incidence rates to uncover epidemiological findings. Oddly enough, KD seemingly appeared simultaneously across Japan and North America in the 1960s.

KD is an acute, self-limited, systemic, pediatric vasculitis. The disease primarily affects young children; 80% of all cases occur in children between 6 months and 4 years of age. Once infected, recurrence rates are low: roughly 4%. Left untreated, KD becomes quite dangerous. As the disease progresses, aneurisms and occlusions may develop and lead to congestive heart failure, stroke, and sudden death. It is considered the leading cause of acquired heart disease among children in North America and Japan. In general, it has a peak incidence rate that coincides with waning maternal approximately (roughly 9-11 months of age) and disproportionally affects males (1.5-1.7:1). In Europe, KD is particularly rare, with an incidence rate of about 5 per 100,000 children. It is more common in the US than Europe, affecting about 9 to 19 per 100,000 children annually, with higher rates seen in people of Asian and Pacific Island descent (32.5 per 100,000). Some reports link it to higher rates of cardiovascular complications in older children and in Hispanic populations.

In Japan, KD is not particularly rare. In fact, a recent report indicates rates may actually be increasing. From 2009 to 2010, rates of KD in children (0-4 years of age) increased from 206.2 to 239.6 per 100,000 children. In 1986, Japan declared an epidemic when the rates of KD approached 176.8 per 100,000 children. However, recent rates of KD are far higher than those reported in 1986. KD is intrinsically linked to the seasons in Japan, with higher incidence during the winter months and lower incidence during the summer. An infectious agent has long been suspected, although no particular agent has been identified. KD is a complex multifactorial disease because individual susceptibility is influenced by both the environment and genetics.

Genetic Susceptibility

CD40LG Gene

Currently, 22 polymorphisms of the CD40LG gene are thought to be associated with the immunopathogenesis of KD. CD40LG belongs to a family of genes called CD molecules and is also a member of the tumor necrosis factor superfamily. CD40LG encodes a protein: the CD40 ligand, or CD40L. CD40L interacts with receptors on the surface of immune cells that are essential in mounting a humoral immune response. CD40L is expressed in a wide range of immune cells, including activated T and B cells, granulocytes, macrophages, and platelets. CD40L can induce B cell proliferation, immunoglobulin class switching, and antibody secretion. Approximately 50% of B cells have CD40L in vesicles and can transport this ligand to their surface for cellular activation. This ligand-receptor complex is essential for the formation of immunoglobulin G, A, and E.

ITPKC Gene

A second gene associated with KD is the ITPKC gene. ITPKC is a protein-coding gene that is responsible for encoding the inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) enzyme. The ITPKC enzyme is a modulator of calcium homeostasis and is involved in theCa2+/NFAT signaling pathway. The nuclear factor of activated T cells (NFAT) is a family of transcription factors that regulate T cell activation. These proteins not only regulate the activation of T cells but are essential to their differentiation and the development of progenitor cells. NFATs are essentially calcium-dependent transcription factors, and mutations in the ITPKC gene lead to diminished enzyme function. It is theorized that this reduced functioning may lead to excess T cell activity, resulting in inflammation, damage to blood vessels, and other signs and symptoms of KD.

China’s Agriculture

It is thought that KD may be an autoimmune disease, and studies into its pathogenesis suggest as much. There are a number of immunoregulatory changes, such as excesses in circulating CD4+ and CD8+ T cells, elevated levels of activated monocytes, and circulating B cells that spontaneously produce immunoglobulins. And unlike viral or bacterial infections that start at some epicenter, emanating outward in specific patterns with a route of transmission of either person-to-person or carrier-to-person, KD differentially infects vast groups of people spontaneously and over large geographic areas, suggesting a single infectious agent such as an allergen. However, unlike most allergens, KD is more active during winter months.  

A recent report in the Proceedings of the National Academy of Sciences attributed KD to an infectious agent originating in a highly cultivated region of northern China. Using existing data regarding KD outbreaks in Japan from 1977 to the present, and matching that with known wind patterns, they created computer models. Using these models, they found that incidents of KD in Japan coincide with wind patterns originating from northeastern China, which is the country’s main cereal grain–growing region. They also collected air samples in Japan during the KD season in an attempt to identify the infectious agent. Samples from that endeavor identified a genus of yeasts (Candida) as the most prominent microbe collected. Candida is a common species and it is responsible for the majority of fungal infections worldwide, including thrush, yeast infections, and the very dangerous candidemia. Whereas it is too early to say that Candida is the causative agent for KD, finding the route of transmission is paramount and that may have been achieved.

Reference

1. Bayers S, Shulman ST, Paller AS. CME: Kawasaki disease. Part 1. Diagnosis, clinical features, and pathogenesis. J Am Acad Dermatol. 2013;69(4):501.e1-501.e11. http://www.jaad.org/article/S0190-9622(13)00713-5/abstract.
2. CD40LG. Genetics Home Reference website. Reviewed October 2008. http://ghr.nlm.nih.gov/gene/CD40LG.
3. Hogan PG, Chen L, Nardone J, Rao A. Transcriptional regulation by calcium, calcineurin, and NFAT. Genes & Dev. 2003;17:2205-2232. http://genesdev.cshlp.org/content/17/18/2205.long.
4. Horn DL, Neofytos D, Anaissie EJ, et al. Epidemiology and outcomes of candidemia in 2019 patients: data from the Prospective Antifungal Therapy Alliance Registry. Clin Infect Dis. 2009;48(12):1695-1703. http://cid.oxfordjournals.org/content/48/12/1695.full.
5. ITPKC. Genetics Home Reference website. Reviewed June 2011. http://ghr.nlm.nih.gov/gene/ITPKC.
6. Miller MM, Miller AH. Incomplete Kawasaki disease. Am J Emerg Med.2013;31:894.e5-894.e7.
7. Nakamura Y, Yashiro M, Uehara R, et al. Epidemiologic features of Kawasaki disease in Japan: results of the 2009–2010 nationwide survey. J Epidemiol. 2012;22(3):216-221.
8. Onouchi Y. Molecular genetics of Kawasaki disease. Pediatr Res.2009;65:46R-54R. http://www.nature.com/pr/journal/v65/n5-2/full/pr2009122a.html.
9. Rodó X, Curcoll R, Robinson M, et al. Tropospheric winds from northeastern China carry the etiologic agent of Kawasaki disease from its source to Japan. PNAS. 2014:111(22):7952-7957.
10. Sabatier I, Chabrier S, Brun A, et al. Stroke by carotid artery complete occlusion in Kawasaki disease: case report and review of literature. Pediatr Neurol. 2013;49(6):469-473.
11. Sánchez-Manubens J, Bou R, Anton J. Diagnosis and classification of Kawasaki disease. J Autoimmun.2014;48-49:113-117.
12. Tiller GE. Kawasaki disease. OMIM website. Updated November 10, 2011. http://www.omim.org/entry/611775?search=kawasaki%20disease&highlight=kawasaki%20disease.
13. Wykes M. Why do B cells produce CD40 ligand? Immunol Cell Biol. 2003;81:328-331. http://www.nature.com/icb/journal/v81/n4/full/icb200347a.html.
14. Xia HJ, Yang G. Inositol 1,4,5-trisphosphate 3-kinases: functions and regulations. Cell Res. 2005;15:83-91. http://www.nature.com/cr/journal/v15/n2/full/7290270a.html.