Article Title: Kawasaki Syndrome in India: Increasing Awareness or Increased Incidence
Authors:
- Howard I. Kushner, Ph.D.
Nat C. Robertson Distinguished Professor &
Director, MPH Program
Department of Behavioral Sciences & Health Education
Rollins School of Public Health
Emory University
1518 Clifton Road, NE, 5th floor
Atlanta, GA 30322 USA
- Jane C. Burns, MD
Professor and Chief, Division of Allergy, Immunology
Dept. of Pediatrics-MC 0830
UCSD School of Medicine
9500 Gilman Drive
La Jolla, CA 92093-0830 USA
- Rupert Macnee
Project Director
Kawasaki Disease Foundation
Blaine, Washington 98320 USA
First Author Email:
Classification: Review Article
Total Pages: 25
Number of Table: 0
Number of Figures: 0
Special Requests: none
Suggested Reviewers, Indian
- Surgit Singh, MD
Additional Professor of Pediatric Allergy and Immunology,
Department of Pediatrics,
Advanced Pediatric Centre,
Post Graduate Institute of Medical Education and Research,
Chandigarh, India-160012.
- Raju Khubchandani, MD
Pediatric Rheumatology Clinic
Jaslok Hospital
Mumbai, India
- Vikas Kohli, MD
Consultant Pediatric Cardiologist Apollo Indraprastha Hospital
New Delhi, India
Cover Letter:
Dr. Peush Sahni, MD
Editor-in-Chief,
National Medical Journal of India
All India Institute of Medical Sciences
New Delhi 110029, INDIA
Dear Dr. Sahni,
Dr. Jane C. Burns (Department of Pediatrics, University of California, San Diego) and I recently completed a manuscript entitled “Kawasaki Syndrome in India: Increasing Awareness or Increased Incidence.” This manuscript is a much expanded and detailed exposition of the general issues we raised in an editorial, “Impressions of Kawasaki Syndrome in India,” which appeared in Indian Pediatrics, (43, 17 November 2006). We think this new article, based on our interviews with pediatricians throughout India, but focusing on 5 centers, raises worthwhile and important issues that move beyond those in the editorial and we hope it will be of interest to a wide range of Indian practitioners and researchers. We believe that the NMJI would provide the most appropriate venue for our article. Our paper also supplements and provides support for a recent excellent review article published in NMJI by Singh and Kansra (Kawasaki disease. Nat Med J India2005; 18: 20-24) that suggested that KS is grossly underdiagnosed in India.
In particular, the paper examines whether the increasing reports of Kawasaki Syndrome (KS) throughout India reflects a heightened awareness of KS or an actual increase in KS incidence. The answer to this question has important consequences for the Indian pediatric population and its health care delivery system. Whether or not the incidence is increasing and has not yet plateaued or the increase in cases is a result of heightened awareness, the resultant KS disease burden is likely to pose a significant challenge to the health care system in India in the coming years due to the high cost of treatment and the potential for lifelong cardiovascular sequelae. Moreover, elucidating the factors that have contributed to the increased recognition of KS in India may provide useful insights for the continuing search for the etiology of KS worldwide. Finally, the paper suggests that increased awareness and incidence of KS in India should be viewed in the context of the issues of economic development as they may interact with what has been described as the “hygiene hypothesis” and its impact on children at risk for KS in India. We believe that an examination of the increase in KS in India (whether due to awareness or incidence or a combination of both) has important implications for the often noticed fact that KS seems to have the highest incidence in developed countries. Thus, attempting to understand what appears to be taking place throughout India, can provide important clues for understanding the etiology KS beyond India, in both developed and developing countries.
Because our methodology relies heavily on interviews with practitioners, it is different from the articles that have appeared in NMJI and indeed from our previous publications on a variety of aspects of KS. However, we hope that these interviews help open a unique door, adding additional insights into dealing with the possible etiology of KS, which has eluded researchers for almost 50 years.
We believe that this submission best fits into your category for review articles. We hope, that if you find our approach and content suitable, that you will be willing to make allowances about its length, which, given our methodology, is larger size than your normal articles. We have already reduced its size, but as attached, the paper is 5800 words with 47 references (but most of these references are to individual interviews). We do believe that NMJI is very best venue in the world for this paper, but of course, you will be the final judge about whether it is appropriate for NMJI and whether or not to send it to referees.
In any case, the attached version is formatted for the criteria set out on your home page. In addition, if you decided to go forward with this paper, we do have, if you require them, signed consent forms and releases from all the persons we quote directly or indirectly.
With Best Regards,
Howard I. Kushner, Ph.D.
Nat C. Robertson Distinguished Professor &
Director, MPH Program
Department of Behavioral Sciences & Health Education
Rollins School of Public Health
Emory University
1518 Clifton Road, NE, 5th floor
Atlanta, GA 30322
Authors’ Declaration:
Contributors: HIK and JCB performed all the interviews that formed the basis of this work and wrote the manuscript in joint writing sessions. RPM organized the trip to India and videotaped the interviews and, along with HIK organized the transcripts into the web-based archive. Researchers can access this archive by permission through the KD history website:
Funding: This research was funded by a grant from the National Institutes of Health, National Library of Medicine (G13LM007855) to the Kawasaki Disease Foundation.
Title Page:9 Oct 2007 formatted for The National Medical Journal of IndiaKawasaki Syndrome in India:
Increasing Awareness or Increased Incidence?
Howard I. Kushner1
Rupert P. Macnee2
Jane C. Burns3
© 2007
1 Department of Behavioral Sciences & Health Education, Rollins School of Public Health, Emory University, Atlanta, GA, 30322, USA.
2 Project Director, Kawasaki Disease Foundation India Project, Blaine, WA, 98320, USA.
3 Department of Pediatrics, University of California School of Medicine, San Diego, and Rady Children’s Hospital, San Diego, CA, 92093, USA.
Keywords:Kawasaki Syndrome (KS), India, coronary artery aneurysms, epidemiology, pediatric cardiology.
Correspondence to:Howard I. Kushner, PhD, Nat C. Robertson Distinguished Professor, Rollins School of Public Health, Department of Behavioral Sciences & Health Education, Emory University, 1518 Clifton Road, NE, 5th Floor, Atlanta, GA 30322, USA. E-mail:
ABSTRACT(135 words)
Reports of Kawasaki Syndrome (KS) throughout India are increasing. This paper examines whether these reports reflect an increasing awareness of KS or an increase in KS incidence. The answer to this question has important consequences for the Indian pediatric population and its health care delivery system. Whether or not the incidence is increasing and has not yet plateaued or the increase in cases is a result of heightened awareness, the resultant KS disease burden is likely to pose a significant challenge to the health care system in India in the coming years due to the high cost of treatment and the potential for lifelong cardiovascular sequelae. Moreover, elucidating the factors that have contributed to the increased recognition of KS in India may provide useful insights for the continuing search for the etiology of KS worldwide.
INTRODUCTION
Kawasaki Syndrome (KS) is the most common cause of acquired pediatric heart disease in the developed world.[1] Untreated children with KS are at risk for development of potentially fatal coronary artery aneurysms. As we have shown in previous publications, there have been two distinctive epidemiological patterns for the emergence of KS. In Europe and North America, KS existed in the pediatric population for more than a century, classified as atypical forms of different diseases.1 When KS finally was recognized as a distinct entity, the incidence was low: for the continental U.S. the rate varies between 9 and 20/100,000 children under 5 years of age and for Japanese Americans living in Hawaii 198/100,000 in children less than 5 years of age.2 In contrast, in Japan, KS seems not to have existed prior to the early 1950s when cases that were in retrospect likely to have been KS were first reported. These were followed by three nationwide epidemics, which leveled off at the relatively high current endemic rate of approximately 200 per 100,000 in children less than 5 years [of age]3,4 Such an epidemiological pattern suggests a novel exposure in a highly susceptible population that initiates the KS immune response.
Cases of Kawasaki Syndrome (KS) have been increasingly reported from India in the last several years.5-8 In what follows we examine whether the identification of this illness on the Indian subcontinent resembles the European/North American experience, where KS existed hidden in other diagnostic categories, or the Japanese model, where the KS agent(s) was newly introduced into a susceptible population. This distinction has important consequences for the Indian pediatric population and its health care delivery system. There are an estimated 120 million children less than 5 years of age in India.9 Depending on whether the host genetic factors and environmental conditions are more similar to the U.S. or Japan and extrapolating from the KS rates in those two countries, one could expect between 24,000 and 240,000 new KS cases annually in India. Whichever prediction turns out to be correct, the KS disease burden is likely to pose a significant challenge to the health care system in India in the coming years due to the high cost of treatment and the potential for lifelong cardiovascular sequelae.
Methods
For more than 40 years researchers have attempted and failed to locate the etiological agent(s) of KS. Despite numerous promising leads and impending breakthroughs, no responsible agent has been identified. At one time or other a variety of infectious bacteria, viral, and rickettsial organisms have been suspected. Immunological agents such as bacterial toxin-mediated superantigens also have been implicated. Additional candidates have included heavy metals (mercury) and allergens such as anionic detergents in carpet cleaners and house-dust mites.10 In an attempt to search for clues about the etiology of KS, in 1998 we launched an interdisciplinary investigation of the emergence of KS in Japan and the West. The results of these investigations have appeared in a series of published articles.11,4,1 Based on our research experience in Japan and the West, we decided to conduct a similar investigation in India. Over a 2-week period in February 2006 we examined suspected and confirmed KS patients, interviewed 47 parents of children diagnosed with KS, and interviewed 52 experienced, senior pediatricians, trainees, cardiologists, and other subspecialists in four different geographic locations in India (Chandigarh, New Delhi, Trivandrum, and Mumbai/Thane). These were supplemented by teleconferencing with pediatricians in Bangalore, Kolkata, and Hyderabad. We also reviewed the English-language literature on KS in India beginning in 1977 with the first reported case.12
We addressed the question of whether the increased diagnosis of KS in India represents the emerging recognition of an illness that has been obscured prior to the 1970s by mis-classification as other pediatric disorders, or whether KS is actually new to India. In our interviews, we asked physicians questions about where and when they saw their first patient who, in retrospect, fulfilled the criteria for KS. We also asked under which categories might patients with KS be misclassified and if the current increase in numbers of KS patients in India is related to increased case ascertainment or an actual increase in KS incidence.
RESULTS
There was a consensus among the physicians that the number of diagnosed cases of KS is increasing in India. At first, many physicians responded that increased awareness of the syndrome accounted for the growing incidence and that KS most likely had been misclassified as drug reactions or viral or bacterial toxin-mediated illness. However on further reflection, most, but not all, of the interviewees thought it unlikely that KS cases had been missed in large numbers previously and that the recent increase in KS diagnoses also reflected an actual increased incidence.13,14
DISCUSSION
The earliest report of KS in India was published in 1977 by Dr. Arvind Taneja, a pediatrician in New Delhi.12 Interviewed in February 2006, Taneja recalled that he had seen his first case of KS at the emergency room at Boston Children’s Hospital while a junior resident in pediatrics. When he returned to India in the fall of 1976, his father who was also a pediatrician took him to see a colleague’s hospitalized 5-year-old boy who had presented with a persistent fever for 12 days, a rash, stomatitis, and red eyes. The diagnosis was Stevens-Johnson syndrome. “I saw this child,” Taneja related, “and the memory of what I had seen in Boston flashed back.” Taneja recalled that “what really triggered me off . . . was the extreme edema that I was seeing on the backs of his hands and feet.” The child’s rash and the finding of sterile pyuria and elevated liver enzyme levels added weight to Taneja’s diagnosis. “Initially my seniors in the profession didn’t believe me, but then when things kept fitting in . . . they came around” to my view. The child was put on aspirin, but “his fever didn’t come down and this child didn’t get better.” Taneja was unable to follow this case and the outcome remains unknown.14
When asked if he believed that KS was new to India in 1977 or had been hidden in other diagnoses, Taneja replied that “my feeling is it is ascertainment rather than an actual increase. I think it’s been better recognition of a constellation of signs and symptoms.” But on reflection he related that his father who “was a very astute clinician,” who had been practicing pediatrics in Delhi since 1952, “told me he hadn’t seen something like Kawasaki earlier to when we described it.” According to the senior Taneja, “I might have missed a patient or two, but I haven’t missed a large number of patients like this.”
Taneja’s pediatric partner for 30 years, Dr. Shyam Kukreja, added that the number of cases has “probably increased” because he and Taneja had been “aware of the disease for the last 20 years” and until recently “in our own practice [we have] tended to more patients in [the] last 2, 3 years as compared to what we used to see in [the] last 15, 20 years.” For instance, “there used to be one case in a year,” but now, according to Kukreja, “suddenly there were about three cases from my own practice 3 years ago. And we had about four, five cases in this year only.”14
Taneja’s initial reaction that the recent rise in KS diagnoses represented an ascertainment bias was repeated by other senior Indian pediatricians, who often replied with the phrase, “The eyes cannot see what the mind does not know.”
Dr. Surjit Singh, Professor of Pediatric Allergy and Immunology, at the prestigious Post Graduate Institute of Medical Education and Research (PGI) in Chandigarh, India, and an expert on KS in India,5,6,15is persuaded that there is “no real increase, there’s just an apparent increase related to increased awareness” of KS. “It’s just that we’re becoming more and more aware of this condition.” Singh admitted that he did not “have any hard data to support” his view, but he based this hunch partly on information from his “dermatology colleagues” who “are now quite attuned to making a diagnosis of Kawasaki disease and they say that, previously they never thought of this condition” and had been “labeling these patients as Stevens-Johnson syndrome.”16
Singh’s view was echoed by his former postgraduate student Dr. Jyotsna Sachdev, now a private practitioner. In medical school, Dr. Sachdev had “heard of Kawasaki, but,” she recalled, “I doubt that we saw a case during our residency program.” According to Sachdev, the 2005 visit to Chandigarh by Dr. Tomisaku Kawasaki served to increase both physician and public awareness of KS, eliciting extensive publicity including newspaper articles. “That is when, I think, a lot of us again got sensitized towards Kawasaki.” She was convinced that the increased numbers of cases was “just that we’re diagnosing it more. . . . I can look back and think of cases now that could have been and we missed. I said probably it’s a viral, watch and wait, everything cleared off, we didn’t do any specific diagnostics. So I feel we’re just picking it up more.”17
Dr. Jayant Banerji, a Chandigarh physician whose child was diagnosed with Kawasaki disease, believed that KS was “under diagnosed” because “there is [a] fair degree of unawareness about this in non-pediatric doctors.” Banerji also thought “that there’s a sort of denial in parents and doctors when it comes to KD. They don’t want to know and they make a lot of visits and when somebody tells them it’s not KD that’s the one they believe.”18
Singh’s current resident fellows were less persuaded that awareness alone accounted for the increasing reports of KS. This view was perhaps best expressed by one of Singh’s pediatric fellows, Dr. Sunil Ghelani, who asserted that “such sudden increase could not be just attributed to awareness” because KS “has always been there in our textbooks” and “doctors in tertiary care centers always knew of this disease, but the sudden increase in the number of cases . . . could be partly that the disease is on the rise and hence the awareness.” But Ghelani was adamant that “just pure increase in awareness would not increase the number of cases. I mean, even 10 years back it was there in the textbook and people knew the disease.” Clearly, the “disease is also on the rise and hence we’re seeing more cases.” Although “it could be awareness is leading to more diagnosis, but the disease is also definitely on the rise.”19