Article Title: Kawasaki Syndrome in India: Increasing Awareness or Increased Incidence

Authors:

1. Howard I. Kushner, Ph.D.Nat C. Robertson Distinguished Professor & Director, MPH ProgramDepartment of Behavioral Sciences & Health Education Rollins School of Public HealthEmory University1518 Clifton Road, NE, 5th floorAtlanta, GA 30322 USA

2. Jane C. Burns, MDProfessor and Chief, Division of Allergy, ImmunologyDept. of Pediatrics-MC 0830UCSD School of Medicine9500 Gilman DriveLa Jolla, CA 92093-0830 USA

3. Rupert MacneeProject DirectorKawasaki Disease FoundationBlaine, Washington 98320 USA

First Author Email: hkushne@emory.edu

Classification: Review ArticleTotal Pages: 25Number of Table: 0Number of Figures: 0Special Requests: none

Suggested Reviewers, Indian

1. Surgit Singh, MDAdditional Professor of Pediatric Allergy and Immunology,Department of Pediatrics,Advanced Pediatric Centre,Post Graduate Institute of Medical Education and Research,Chandigarh, India-160012.

2. Raju Khubchandani, MDPediatric Rheumatology Clinic Jaslok Hospital

Mumbai, India

3. Vikas Kohli, MDConsultant Pediatric Cardiologist Apollo Indraprastha HospitalNew Delhi, India

Cover Letter:

Dr. Peush Sahni, MDEditor-in-Chief, National Medical Journal of IndiaAll India Institute of Medical SciencesNew 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 India 2005; 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 ProgramDepartment of Behavioral Sciences & Health Education Rollins School of Public HealthEmory University1518 Clifton Road, NE, 5th floorAtlanta, 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:

http://www.emory.edu/CHCS/p_histmed_Kawasaki.htm

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 India

Kawasaki 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:

hkushne@emory.edu

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

1 Throughout this paper we have used the term “Kawasaki Syndrome (KS)” rather than “Kawasaki Disease” (KD) because the etiology is idiopathic and diagnosis is made through an identification of a combination of clinical signs and some symptoms. Strictly speaking, to label a condition as a disease requires a known etiology identifiably by a laboratory test.

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,5,6,15 is 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

This view was supported by a senior pediatric cardiologist, Dr. Savitri Shrivastava,

Professor at Escorts Heart Institute and Research Centre in New Delhi. Shrivastava, who has

been in practice since 1973, recalled that until 1990 or 1992 her pediatric cardiology group had

almost no referrals of patients “diagnosed as Kawasaki.” At the time Shrivastava was Professor

of Cardiology at the All India Institute of Medical Sciences, and she remembered that her

cardiologist colleagues were “looking for Kawasaki, but not finding any.” They even asked

pediatricians why they were not referring “any cases [of] Kawasaki to us to look for the

aneurysms. So they would tell us that, well we are looking for it but we are not finding any

positive cases.” All that changed gradually “in [the] last 10 years, the diagnosis of Kawasaki is

more often made by pediatricians.” Shrivastava believed that “awareness is definitely more

increased. We have more centers which can probe the coronary arteries by echo.” But she also

insisted that part of this represents a real increase. Perhaps because of increasing travel

“Kawasaki has come to us.”20

Dr. Subhash Arya, Director of the Center for Child Health at Sir Ganga Ram Hospital in

New Delhi and a practitioner for more than 40 years, noted that he and others of his generation

had been reading about KS for more than 30 years, but never saw any cases until recently.

“Retrospectively, I think there were some other cases also, which we thought of Kawasaki. We

didn’t label them Kawasaki, but retrospectively, I would have labeled them Kawasaki because

not everything was there, but once we started to see more and more atypicals, I realized you

don’t get the cluster description here.” Now, there were increasing numbers of atypical cases of

older children “6 years, 8 years, even 10 years” old.21

Most practitioners initially responded to queries about what accounted for the spike in KS

diagnoses, similarly to pediatrician Dr. Kartik Nagesh of Bangalore’s Manipal Hospital: “It’s

more the awareness . . . I think it’s the awareness the disease has been there possibly all along.”

But, when asked to describe the first case he had seen, Nagesh, who trained at the PGI in

Chandigarh and had been in practice since 1983 and who had seen his first case in 1999,

recounted that the presentation was so striking that he would never forget it. “I do not think that

during my career in medical school or in postgraduate medical school neither subsequently

would I have missed something” like that.22

Pediatric cardiologist Dr. Vikas Kohli at New Delhi’s Apollo Hospital found much

resonance throughout India in Dr. Nagesh’s response: “Almost everybody said that--the same

thing and probably I'm getting the impression that it [increased numbers of KS cases] started

somewhere in the late ’90s when they started seeing five, six cases.”23 Dr. Kohli has been

actively developing a registry of cases of KS. According to Kohli, KS in India today very much

resembles the Japanese experience in the 1960s, where there were 20 cases reported, then there

were 50 cases, all of a sudden there were thousands of cases. “I think we are at that point in

India,” Kohli said. “When I spoke to Dr. Kawasaki when he came to Chandigarh, I told him I

have 32 patients in the last 2 years. He said, someone here has told me 91, somewhere else I

read a report of 25 [patients], I think India is in an epidemic zone of Kawasaki. Those were his

words.”24

Epidemic zone or not, there are a number of factors that make it difficult to determine

whether or not KS is new to India or, until recently simply missed. These include the continuing

skepticism of many Indian practitioners to acknowledge the existence of KS, coupled with the

resistance of Indian parents to accept the diagnosis when made. This skepticism and resistance

are not frivolous, but rather reflect the complexities and history of Indian society and experience,

especially with childhood illnesses.

Dr. Naveen Jain, a pediatrician at Trivandrum Medical College in India’s southern most state, Kerala,

recalled this physician skepticism in the 1990s. Jain, who trained under Travandrum’s Dr. Noel

Narayanan, who identified the first case of KS in Kerala in 1994,25 reported that “there were people

who would giggle” behind Dr. Naraynan’s back “and say that we are trying to introduce a disease into

the society that doesn’t exist . . . . The name itself was so unfamiliar to many people that it was really

not accepted in the first few months.”26

In fact, we found that an undercurrent belief remained among Indian physicians that KS

was over-diagnosed in centers like the Trivandrum Medical College and the PGI in Chandigarh.

“There are many doctors who feel that we are over diagnosing Kawasaki Disease,”

acknowledged Dr. Singh at Chandigarh’s PGI. “This is a fact that many of them feel that we are

over diagnosing Kawasaki Disease and that any child with fever and rash if he’s referred to our

institution is likely to get a diagnosis of Kawasaki Disease.”16 “Those pediatricians,” according

to Dr. Raju Khubchandani, pediatric rheumatologist and KS expert at Jaslok Hospital and

Research Center in Mumbai, “are more the slightly senior age group who are probably less open-

minded who think that now we are going overboard and sometimes diagnosing more than we

should be.”27 However, Khubchandani is convinced, “that does not happen” because “there is an

inbuilt safety wall over here to diagnose Kawasaki. And that inbuilt safety wall is the cost of

IVIG.” For instance, “to prescribe anti-TB drugs or anti-malaria drugs for somebody for 3 days

or 2 days costs them peanuts,” but as Khubchandani pointed out, the cost of IVIG is “more than

the per capita income of a given Indian family, assuming per capita income is around 500 US

dollars per annum for . . . a single dose.” Moreover, “often pediatrics is not covered by

insurance. So this is all often self-pay and therefore we better be very, very sure--as sure as we

can be to ourselves--before you finally commit to the patient and say that this is I think where

you need to go.”27

Poverty is a constraint on diagnosing KS in other ways as well. As PGI-trained

pediatrician Dr. Srikanta Basu pointed out, if a child is brought to hospital, the whole family will

come along. “Most of them are daily wagers--they lose their food and everything.” As a result,

many children with KS are never seen by physicians. Poverty, Basu notes, has “many practical

implications. For simple rash and fever, they may not be coming to hospital. They go to a local

private practice, not even an allopathic doctor, get some medicines or something else.”17

As one PGI trainee Dr. Kunal Gupta elaborated, the reason for so many missed diagnoses is

connected to Indians’ experiences with childhood illnesses, especially, those involving fever. “The

problem in a developing country like India, where many people are fighting to get their basic needs,

there are so many fevers, there are so many episodes of fevers and there are so many common causes

of fever that for the parents to take at the first moment a disease like Kawasaki as the diagnosis may

be very difficult.” In fact, Gupta added, this is so “even with educated families” where “it is not

uncommon for a child to fall ill with fever every 4 months.” As a result even relatively well-off

parents, who bring their children for treatment, resist the diagnosis: “For parents to come to an

institute and to be told such an uncommon disease they’re diagnosed like Kawasaki Disease is very

difficult. This is one of the basic reasons for parents denying--like they’re receiving a shock, like

what is this Kawasaki. This is the basic reason for their refusing to take the diagnosis.”28

Physicians’ resistance to the diagnosis is a factor as well. Like others, Khubchandani admits he

initially doubted the existence of KS. “I wasn’t skeptical, he remembered, “I was ignorant . . . what

the mind didn’t know the eye--yeah.”29 Diagnosing his first case made him into a believer. “I’ve

always maintained that the most difficult Kawasaki to diagnose is your first case. Nobody’s held

your hand there. You’ve never seen it before and you’re worried, and it’s a purely clinical

diagnosis.” Because there are no reliable laboratory tests to indicate KS, “it’s purely a judgment call”

and “the first time you need somebody to lead you through it.” But, “once you diagnosed your first

case, you will never forget it.”27

All of these factors make it difficult to determine whether the increasing diagnosis in the past several

years results from changes in awareness of KS, spurred on by the declining resistance of physicians

and patient families, or from an actual increase in the number of cases. “The next consequential

question,” according to New Dehli pediatric cardiologist Vikas Kohli is “why in the ’90s we started

seeing Kawasaki.” Part of the answer, Kohli believes, is modernization: “A lot of things changed in

India in the ’90s.” India “is still changing and you can see that there are parts of the society which are

not very different from the Western world. And then there are parts which are left way behind. So

when that part of society also reaches this level, will we see more Kawasaki? Will it be rampant?

We will not just see 30 or 60, but maybe we’ll see 300 and 600. . . as happened in Japan.”30

ECONOMIC DEVELOPMENT, SOCIAL CHANGE, AND KS

One cannot ignore the impact of the social and economic transformations that have shaped India since

the mid-1990s. The growth of a substantial middle class (approximately one-third of the population)

with increasing access to medical care and, more important, to medical information, has influenced

the acceptance, increased diagnosis, and perhaps the actual incidence of KS. One should not

underestimate the influence of social policies and economic development on both increased

awareness and actual disease incidence. As Dr. Sachdev noted, when a child is ill, “it is taken as the

will of God.” Given the economic and social cost of treatment to the entire family, elaborated above

by Dr. Basu, even when faced with the loss of a child, according to Sachdev “they might say that was

the will of God.”17

But all this is rapidly changing. The impressive economic development which has taken

place in India beginning in the mid-1990s has enabled middle-class Indians to comply with the

national one child per family policy. As Indian families reduce their size, especially to one child,

it stands to reason that each child’s health becomes a much greater concern and middle-class

parents in India may adopt a more proactive response to their child’s fevers and rashes. This will

clearly have an impact on recognition of KS, as more children with KS are brought to clinic who

might otherwise have been missed.

Dr. Subroto Chakrabartty, of Rama Krishna Mission Hospital in Kolkata, reports more awareness in

his 17 years as a pediatrician. In a recent retrospective study of all 25 diagnosed KS cases treated at

Kolkata’s Institute of Child Health from September 2001 to March 2005, Chakrabartty and his

colleagues reported that Indian patients often received delayed diagnoses and, as a result, in “more

than 50% [of] cases, signs like unilateral cervical lymphadenopathy, rash, and edema were absent.”

Although these children “consistently present . . . with persistent fever, extreme irritability, non-

purulent bulbar conjunctivitis and mucositis,” 56% of their cases “did not meet the criteria for classic

KD; at the same time they were not incomplete/atypical cases.” In fact, “84% presented beyond the

first week” and “are often diagnosed late and are treated as “Pyrexia of Unknown Origin.” As a result

of these delays Chakrabartty and colleagues found a “definite increase in morbidity with delay in

treatment like development of coronary aneurysms and myocardial complications (like myocarditis

and arrhythmias)” in India. These investigators urged practitioners to make diagnoses in the context

of “the ground realities throughout the country.” Nevertheless, Chakrabartty and his team were

convinced that “the incidence of KD is increasing in India.”31 As he elaborated in a telemedicine

interview from his office at Rama Krishna Mission Hospital in Kolkata, “I strongly feel that this

Kawasaki Disease is increasing and we need to do something about it.”32

Similar to Chakrabartty, Dr. Sreekanth Raghavan at Hyderabad’s Apollo Hospital has

noticed “a lot of atypical Kawasaki presentations. The classical form is . . . very difficult to see,

I do not know whether the reason is because the type of referral we end up getting because a lot

of these patients end up coming later, or whether it is a general lack of awareness of Kawasaki in

our population. That we are probably missing some of the patients that we should be picking up

in the first place.” Raghavan’s patients often were diagnosed relatively late after many acute

signs had come and gone, but his patients had fewer coronary artery abnormalities than

Chakrabartty and colleagues found. “They don’t usually have the maximum incidents of

aneurysms,” wrote Raghavan, that “I have seen while I was in Chicago [where he trained under

the supervision of KS expert Dr. Stanford Shulman at Northwestern University] and also

Detroit . . . where I had actually seen a significant amount of these aneurysms. But I think

nowadays the amount of patients who develop aneurysms for some reason in this part of the

world has been significantly lesser.” Raghavan noted that his patients had a “very high

presentation of fever with irritability rather than typical rash. For some reason we don’t end up

seeing much of the rash either.” Nevertheless, Raghavan, like the others, was persuaded that the

increase was also real: “I think it goes both ways. I think it is also increased awareness because

we have been talking about it now. But also I think there’s also increased incidence” and that

they weren’t even seeing the “tip of the iceberg. . . So I think there’s a lot more cases out there.

And there may have been an actual increase in the incidence, lately, apart from the fact that the

awareness has increased substantially.”33

Even if “the reported incidence is probably underestimated in many countries as atypical cases are not

included,” write Australian pediatricians David Burgner and Anthony Harnden, evidence indicates

that “in a number of countries the incidence of KD appears to be increasing.” Although Burgner and

Harnden admit that “this may be partly attributable to increased awareness,” they also find that this

“increasing incidence is reported in countries where the disease has been widely recognised for

several years and where a standard case definition is employed and may therefore reflect changing

epidemiology.”34

As Kohli suggests, development also may serve to increase the actual incidence of KS because it may

enable exposure to a novel agent or, as suggested below, increased hypersensitivity of middle-class

Indian children with decreased exposure to traditional childhood infections. According to the

“hygiene hypothesis,” healthier children may actually increase their risk of autoimmunity.35,36 Korean

pediatrician Kyung-Yil Lee and his colleagues recently postulated that KS might be a hyperimmune

reaction in genetically susceptible children that is brought on by economic development and

modernization. Such a scenario, Lee writes, helps explain the emergence of KS in East Asia in the

1960s and 1970s. “It is very intriguing,” notes Lee, “that with the similar ethnic back ground of the

Far East countries, the time of appearance and the incidence rates of KD may be correlated with the

time of the beginning of industrialization and the adoption of a western lifestyle, i.e., in the order of

Japan, Korea, Taiwan and China. In addition, the incidence of KD in these countries continues to

increase steadily.” According to Lee and colleagues, “the environmental factors from the improved

public hygiene or a western lifestyle in industrialization may transform a group of normal microflora

to their variants in the gut, oral cavity or skin of the parents/caregivers of infants and young children.”

Once these variant microflora are colonized, in some young children who have a genetic defect of

proper immune maturation, “the variants fail to induce immune tolerance as self commensals, but

rather, they induce a state of confusion on the immune system as the variants being seen as non-self

or pathogens, leading to a hyperimmune reaction and the manifesting KD.”37 A similar scenario has

recently been hypothesized for India,38 and it is reflected in Kohli’s suggestion that economic

development and modernization are associated with an increased incidence of KS.

That increases in KS follow changes in life styles seems borne out in India’s southern most state,

Kerala. With a literacy rate of more than 90%, Kerala’s population is the most highly educated and

uniformly prosperous in India. Dr. Noel Narayanan, who had recently retired (2005) after serving 32

years as the head of the pediatrics department at Medical College of Trivandrum, told us that one

result of this educational and economic prosperity is reflected in Kerala’s “immunization rate [that] is

more than 87%. . . In the last three decades . . . the diarrheal death due to communicable diseases,

death due to severe malnutrition all these have almost been virtually eliminated. We hardly see any

diarrheal deaths at all. But, new diseases have started coming up then and the dengue fever is

actually a recent disease--illness in our state and Kawasaki Disease again started appearing recently

so I think once some of the diseases have disappeared--whether they have appeared new or whether

we were missing them in the past we are not sure.”39

“I think it’s a relatively new disease,” added Dr. Ashok Kumar, retired professor of pediatrics at

Trivandrum Medical College, now chief of pediatrics at the private Kim’s Hospital. Although he had

been aware of and studied KS as early as1970, when he was a medical student, Kumar noted that he

had not seen many cases even by 1980. “I cannot say,” he added, “but I think it’s a relatively new

disease.”40

Narayanan, who spent 5 years in medical residency in Britain, first at Leeds and then 4 years at the

Royal Manchester Children’s Hospital, identified the first case of KS in Kerala in 1994.25

“Subsequently,” Narayanan told us, “we had four cases in 1995 then about 15 cases in 2000, some 24

cases in 2004 and about 30 cases in 2005.” There was, he told us, “a steady increase in the number of

Kawasaki diseases admitted to our hospital. So we find a sort of a clustering of cases in Trivandrum

because our catchment area is Trivandrum plus adjacent districts.” Narayanan noted, that given its

population (3.1% of India or a population of 38.1 million), Kerala had the highest incidence of KS in

India. “Probably” that is “because of increased awareness, that is what I feel, but it could be possibly

a new infectious agent is around or maybe some unknown trigger is around and probably we are

genetically susceptible people. We do not know. This is something, you know, we really wanted to

find out, why the sort of clustering of cases is occurring in our place.”39

When asked if he retrospectively could recall misdiagnosed cases of KS in Kerala before 1994,

Narayanan characteristically replied, “Your eyes do not see what your mind doesn’t know.” There

were at that time “many other problems to . . . think about. We had diarrhea [and] we had so many

other pediatric diseases, like measles, that have now been controlled.” In fact, Narayanan, like Kohli

in New Delhi, connected declines in childhood mortality and morbidity to the emergence of KS.39

Trivandrum pediatric cardiologist Zulfikar Ahamed concurred, noting that elimination of

other childhood diseases in Kerala had resulted in an increased awareness of KS. In the last

decade, he explained, “the diarrhea ward has now been converted into a general ward.” Ahamed

had been at the hospital “since 1981, 34 years total including post-graduation. So I can tell that

the major difference over [the] last 10 years is that diarrhea has come down. Diarrhea has

practically become non-existent.” Moreover, “polio has slowly disappeared. Measles have

come down dramatically.” As a result his recent postgraduates have not seen measles. “For

them measles is a differential diagnosis of Kawasaki.”41

At their February 2006 monthly meeting at Kaushalya Hospital in Thane, a suburb of

Mumbai, a group of pediatricians discussed the putative increase of KS in India. Looking back

on the years since postgraduate education in pediatrics in the late 1980s, Dr. Suhas Kulkarni, at

Chiranjeevi and Kaushalya Hospitals, believed that some of the many cases of measles he had

treated over the past 20 years could have been KS. These children, according to Kulkarni

“looked indistinguishable from Kawasaki. Fever for more than 5 days, polymorphous rash,

conjunctivitis, and we use to have a lot of complications from measles in those times.” Of

course, at that time he “wouldn’t really think there was Kawasaki.”42 Dr. Prakash Vaidya,

president of the Thane Branch of the Indian Academy of Pediatrics and consultant in pediatrics

at Wockhardt Hospital, Mulund, concurred: “Also I think somewhere down the line we have all

seen MCLS as measles not realizing that this entity is Kawasaki and then we treated it as

measles.”43 Dr. Sandeep M. Kelkar, a pediatrician at Lok and Kaushalya Hospitals

felt that KS was “a recent entity . . . As far as my memory goes I don’t think we had seen

Kawasaki,” before “maybe ’95 onwards. Probably our awareness has also increased, but still if I

recollect I don’t think Kawasaki was there.”44 Because most children in the Thane area would

first be seen by their family physicians, pediatrician Bhavesh Mithiya, at Kaushalya Hospital,

would probably not examine a child until “the eighth day or ninth day. At that time maybe all

the symptoms and signs are a little bit milder or they’ve become severe and then we think of

something which is going on underneath.” This may be the reason why, he explained, “that we

are not quite sure about the diagnosis.”45 But another reason for the lack of awareness of KS, as

pointed out by pediatrician Dr. Shantilal Thakker of Soham Hospital was that from his

experience and that of his patients “the importance of the disease is quite different” because “we

still see it as probably a mild disease as compared to the other disease burden which is there.

How much money to invest on investigation and treatment is also relatively different” than it

may be for American pediatricians and patients.46

CONCLUSION

Whether or not the increased diagnoses of Kawasaki Syndrome throughout India are a

result of increased awareness or an actual increase in disease burden is difficult to determine. In

part the answer is connected to a complex interaction of medical, historical, and cultural issues,

beyond the scope of this paper. But clearly, development, or what may loosely be labeled as

modernization, has played an important role in increasing not only awareness of KS, but also in

possibly creating the conditions that place many more children at risk for KS. Whatever the

reasons, every indication is that KS will continue to present an increasing disease burden on the

pediatric population of India and, it seems, in the developing world.

The issues raised here need to be tested by standard research methods. The incidence of KS can best

be addressed by collaborative efforts to establish KS registries across India to determine the burden of

KS in different regions and among different genetic and cultural groups. Efforts should continue to

increase physician awareness and to encourage research on the characterization of KS in India with

emphasis on possible differences in clinical presentation, disease course, and outcome in Indian

children. One impediment to the evaluation and treatment of cardiovascular sequelae in these

children is the scarcity of pediatric cardiologists to perform echocardiographic imaging of the

coronary arteries. Work by Drs. Narayanan and Ahamed at Trivandrum Medical College to develop

criteria for normal coronary artery internal diameters in southern Indian children should be validated

and adapted for different populations throughout India.47 Educational efforts by parent groups in

Chandigarh and New Delhi to increase lay person awareness of KS serve as a model that should be

emulated in other parts of the country. Similarly, the physician “ready reckoner” developed by Raju

Kubchandani from the Mumbai KS Study group provides easily accessible information for physicians

regarding KS diagnosis and treatment.7 Making such a pamphlet readily available throughout India

will increase physician awareness of KS. Finally, investigating the emergence of KS in India and its

distinct clinical manifestations in Indian children will make important contributions to understanding

this mysterious illness in children throughout the world.

ACKNOWLEDGEMENTS

The authors wish to thank our hosts Dr. Surjit Singh, PGI, Chandigarh; Dr. Vikas Kohli, Apollo

Hospital, New Delhi; Dr. Lalitha Kailas, Head Department of Pediatrics, Medical College,

Trivandrum; Dr. Raju Khubchandani, Jaslok Hospital, Mumbai; and Dr. Prakash Vaidya, Thane,

who generously contributed their time and expertise to this project. We also thank Mr. Gregory

Chen, President of the KD foundation for his support and advise, Dr. John Bastian of Rady

Children’s Hospital, San Diego, for his critical input, and Carol R. Kushner for editorial

assistance.

REFERENCES

Abstracts and transcripts of all interviews cited below are posted or soon will be on our

Kawasaki home page. Available at http://www.emory.edu/CHCS/p_histmed_Kawasaki.htm

1. Kushner HI, Turner CL, Bastian JF, Burns JC. The narratives of Kawasaki disease. Bulletin

History Medicine 2004;78:410-39.

2. Holman RC, Curns AT, Belay ED, Steiner CA, Effler PV, Yorita KL, et al. Kawasaki syndrome

in Hawaii. Pediatr Infect Dis J 2005;24:429-33.

3. Yanagawa H, Nakamura Y, Yashiro M, Ojima T, Tanihara S, Oki I, et al. Results of the

nationwide epidemiologic survey of Kawasaki disease in 1995 and 1996 in Japan. Pediatr 1998;

102:e65-e72.

4. Kushner HI, Bastian J, Turner CL, Burns, JC. Rethinking the boundaries of Kawasaki disease:

Toward the next case definition. Perspectives Biol & Med 2003;46:216-33.

5. Singh S, Bansal A, Gupta A, Kumar RM, Mittal BR. Kawasaki disease: A decade of experience

from North India. Jap Heart 2005;46:679-89.

6. Singh S, Kansra S. Kawasaki disease. Nat Med J India 2005;18:20-24.

7. Khubchandani R, D’Souza S. Kawasaki disease in India. Pediatric Rheumatol Online 2004;2:2.

Available at http://www.pedrheumonlinejournal.org (accessed on 31 Aug 2007).

8. Bagyaraj B, Krishnan U, Farzana F. Kawasaki disease in India. Indian J Pediatr 2003;70:919-22.

9. Adlakha A. Population trends, India. U.S. Department of Commerce, Bureau of the Census

(IB/97-1). Washington, DC, 1997.

10. Lloyd AJ, Walker C, Wilkinson M. Kawasaki disease: Is it caused by an infectious agent? British

J Biomedical Science 2001;58:122-28.

11. Burns JC, Kushner HI, Bastian JF, Shike H, Shimizu C, Matsubara, T, et al. Kawasaki disease: A

brief history. Pediatr 2000;106:e27-e34.

12. Taneja A, Saxena U. Mucocutaneous lymph node syndrome. Indian Pediatr 1977; 14:927-31.

13. Krishnakumar P, Mathews L. Kawasaki disease is not rare in India. Indian J Pediatr 2006;73:

544-45.

14. Interview with Drs. Arvind Taneja and Shyam Kukreja by Burns JC, Kushner HI, Macnee RP.

Apollo Hospital, New Delhi, India, 16 Feb 2006;DVD#22.

15. Singh S. Kawasaki disease: A clinical dilemma. Indian Pediatr 1999;36:871-75.

16. Interview with Dr. Surjit Singh by Burns JC, Kushner HI, Macnee RP. Chandigarh, India, 15 Feb

2006;DVD#15.

17. Interview with Drs. Srikanta Basu and Jyotsna Sachdev by Burns JC, Kushner HI, Macnee RP.

Chandigarh, India, 15 Feb 2006;DVD#15a.

18. Interview with Dr. Jayant Banerji by Burns JC, Kushner HI, Macnee RP. Chandigarh, India, 14

Feb 2006;DVD#11.

19. Interview with Dr. Javitri Srivastava by Burns JC, Kushner HI, Macnee RP. Apollo Hospital,

New Delhi, India, 16 Feb 2006;DVD#20.

20. Interview with Dr. Sunil Ghelani and Pediatric Fellows by Burns JC, Kushner HI, Macnee RP.

Postgraduate Institute of Medical Education and Research, Chandigarh, India, 13 Feb 2006;

DVD#s4,5.

21. Interview with Dr. Subhash Arya by Burns JC, Kushner HI, Macnee RP. Apollo Hospital, New

Delhi, India, 16 Feb 2006;DVD#s20,21.

22. Telemedicine interview with Dr. Kartik Nagesh at Manipal Hospital Bangalore by Burns JC,

Kushner HI, Macnee RP, Kohli V from link at Apollo Hospital, New Delhi, India, 17 Feb 2006;

DVD#24.

23. Discussions with Dr. Vikas Kohli, JC Burns, HI Kushner, RP Macnee. Apollo Hospital, New

Delhi, India, 17 Feb 2006;DVD#24,DVD #20.

24. Remarks by Dr. Vikas Kohli following telemedicine interview with Dr. Kartik Nagesh at

Manipal Hospital Bangalore by Burns JC, Kushner HI, Macnee RP, Kohli V from link at Apollo

Hyderabad, New Delhi, India, 17 Feb 2006;DVD#25.

25. Narayanan SN, Krishna V, Sabarinathan K. Kawasaki disease. Indian Pediatr 1997;34(2):139-

43.

26. Interview with Drs. Ashok Kumar, Neeta Gupta, and Naveen Jain by Burns JC, Kushner HI,

Macnee, RP. Trivandrum Medical College, Trivandrum, Kerala, India, 20 Feb 2006;DVD#s27,

28.

27. Interview with Dr. Raju Khubchandani and pediatric Residents by Burns JC, Kushner HI,

Macnee RP. Jaslok Hospital, Mumbai, India, 22 Feb 2006;DVD#39.

28. Interview with Dr. Kunal Gupta and pediatric Fellows by Burns JC, Kushner HI, Macnee RP.

Post Graduate Institute of Medical Education and Research, Chandigarh, India, 13 Feb 2006;

DVD#s4,5.

29. Interview with Dr. Raju Khubchandani by Burns JC, Kushner HI, Macnee RP. Jaslok Hospital,

Mumbai, India, 23 Feb 2006;DVD#41.

30. Discussion with Vikas Kohli following interview with Dr. Savitri Srivastava by Burns JC,

Kushner HI, Macnee RP. Apollo Hospital, New Delhi, India, 16 Feb 2006;DVD#20.

31. Chakrabartty S, Pramanik S, Thapa R. Difficulties in the diagnosis of Kawasaki disease. Indian

Pediatr 2006;43:728-31.

32. Telemedicine interview with Dr. Subroto of Rama Krishna Mission Hospital, Kolkata, by Burns

JC, Kushner HI, Macnee RP, Kohli V from link at Apollo Hospital, New Delhi, India, 17 Feb

2006;DVD#24.

33. Telemedicine interview with Dr. Sreekant Raghavan, Apollo Hospital Hyderbad by Burns JC,

Kushner HI, Macnee RP, Kohli V from link at Apollo Hyderabad, New Delhi, India, 17 Feb

2006;DVD#25.

34. Burgner D, Harnden A. Kawasaki disease: What is the epidemiology telling us about the

etiology? Int J Infect Dis 2005;9:185-94.

35. Vercelli D. Mechanisms of the hygiene hypothesis--molecular and otherwise. Curr Opin

Immunol 2006;18:733-37.

36. Gwee KA. Irritable bowel syndrome in developing countries--a disorder of civilization or

colonization? Neurogastroenterol Motil 2005;17:317-24.

37. Lee KY, Han JW, Lee JS. Kawasaki disease may be a hyperimmune reaction of genetically

susceptible children to variants of normal environmental flora. Med Hypotheses 2007;69:642-51.

38. Patki A. Eat dirt and avoid atopy: The hygiene hypothesis revisited. Indian J Dermatol Venereol

Leprol 2007;73:2-4.

39. Interview with Dr. S. Noel Narayanan by Burns JC, Kushner HI, Macnee RP. Trivandrum

Medical College, Trivandrum, Kerala, India, 20 Feb 2006;DVD#27.

40. Interview with Drs. Ashok Kumar, Neeta Gupta, Naveen Jain by Burns JC, Kushner HI, Macnee

RP, Trivandrum Medical College, Trivandrum, Kerala, India, 20 Feb 2006;DVD#s27,28.

41. Interview with Dr. Zulfikar Ahamed by Burns JC, Kushner HI, Macnee RP. Trivandrum Medical

College, Trivandrum, Kerala, India, 20 Feb 2006;DVD#28.

42. Interview with Dr. Suhas Kulkarni by Burns JC, Kushner HI, Macnee RP. Kaushalya Hospital,

Thane, India, 24 Feb 2006;DVD#s49,50.

43. Interview with Dr. Prakash Vaidya by Burns JC, Kushner HI, Macnee RP. Kaushalya Hospital,

Thane, India, 24 Feb 2006;DVD#s49,50.

44. Interview with Dr. Sandeep M. Kelkar by Burns JC, Kushner HI, Macnee RP. Kaushalya

Hospital, Thane, India, 24 Feb 2006;DVD#s49,50.

45. Interview with Dr. Bhavesh Mithiya by Burns JC, Kushner HI, Macnee RP. Kaushalya Hospital,

Thane, India, 24 Feb 2006;DVD#s49,50.

46. Interview with Dr. Shantilal V. Thakker by Burns JC, Kushner HI, Macnee RP. Kaushalya

Hospital, Thane, India, 24 Feb 2006;DVD#s49,50.

47. Narayanan SN, Ahamed MZ, Safia M. Cardiovascular involvement in Kawasaki disease. Indian

Pediatr 2005;42:918-22.