Published online September 22, 2008
PEDIATRICS Vol. 122 No. 4 October 2008, pp. e786-e790 (doi:10.1542/peds.2008-1275)
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ARTICLE

Kawasaki Disease in a Pediatric Intensive Care Unit: A Case-Control Study

Samuel R. Dominguez, MD, PhDa,b, Kevin Friedman, MDa, Ryan Seewaldb, Marsha S. Anderson, MDa,b, Lisa Willis, MDa,c and Mary P. Glodé, MDa,b

a Department of Pediatrics, University of Colorado Denver School of Medicine, Denver, Colorado
b Section of Pediatric Infectious Diseases
c Section of Pediatric Cardiology Children's Hospital, Aurora, Colorado


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVES. We conducted a case-control study to ascertain the clinical presentations, risk factors, and clinical outcomes of children who had Kawasaki disease and were admitted to the ICU of our children's hospital.

METHODS. We reviewed charts of all children who had a discharge diagnosis of Kawasaki disease and were admitted to the ICU from 1995 through 2007. For each patient, we identified 3 season-matched control subjects who had Kawasaki disease and were not admitted to the ICU.

RESULTS. We identified 423 patients with Kawasaki disease. Of those, 14 (3.3%) were admitted to the ICU and met our inclusion criteria. ICU admission diagnoses were most commonly toxic shock or septic shock. Thirteen (92.8%) of 14 patients who were admitted to the ICU met criteria for complete Kawasaki disease before treatment. There was no significant difference in age in ICU patients compared with season-matched control subjects with Kawasaki disease. ICU patients were significantly more likely to be female and to have higher band counts, lower platelet counts, lower albumin levels, and higher C-reactive protein values. Time from admission to treatment with intravenous immunoglobulin was delayed in ICU patients. ICU patients were more likely to have intravenous immunoglobulin–refractory disease and require therapy with a second dose of intravenous immunoglobulin, infliximab, or steroids.

CONCLUSIONS. We present a case-control study of patients who had Kawasaki disease and presented severely ill, in shock, and requiring admission to the ICU. These patients frequently were misdiagnosed because of failure to appreciate the full spectrum of disease severity seen in patients with Kawasaki disease. These patients' illnesses was often mistaken for toxic or septic shock, leading to a delay in treatment with intravenous immunoglobulin. Patients who have Kawasaki disease and are admitted to the ICU are at increased risk for intravenous immunoglobulin–refractory disease and may be at risk for development of more severe coronary artery disease.

Key Words: Kawasaki disease • shock • ICU

Abbreviations: KD—Kawasaki disease • CSF—cerebrospinal fluid • IVIG—intravenous immunoglobulin • CRP—C-reactive protein

Kawasaki disease (KD) is an acute self-limited vasculitis that occurs in children of all ages. Because of its potential to cause coronary aneurysms, KD has become the leading cause of acquired heart disease in children in the developed world. It is now recognized that patients with KD can present in a variety of ways, and, in recent years, more children are receiving a diagnosis of "incomplete" KD.1,2

At our institution, we observed a number of children who were admitted to the ICU secondary to hypotension with a presumptive diagnosis of "toxic shock" or "septic shock" and later received a diagnosis of KD. KD was not seriously considered in the initial diagnosis because of the failure to recognize that children with KD could present in shock. Because of these observations, we conducted a case-control study to ascertain the clinical presentations, risk factors, and clinical outcomes of children who had KD and were admitted to the ICU compared with control patients who had KD and were not admitted to the ICU.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Patients with KD were identified from hospital discharge records (International Classification of Diseases, Ninth Revision code 446.1) from 1995 through 2007. This database included billing codes specific for the ICU at our tertiary care children's hospital. Clinical and demographic information was extracted from the medical chart by retrospective chart review. All patients who were included in the analysis were seen by a pediatric infectious disease specialist during their hospitalization and received a diagnosis of KD. In addition, all charts were retrospectively reviewed independently by 3 infectious disease specialists who concurred with the diagnoses of KD. Subsequently, KD cases were classified as complete or incomplete KD on the basis of published standard clinical criteria.2

Case patients were defined as patients who had a discharge diagnosis of KD in their medical chart and who were admitted to the ICU at any time during their initial admission to the hospital. Case patients were excluded when they had positive bacterial cultures from a normally sterile site (blood, urine, or cerebrospinal fluid [CSF]), evidence of focal staphylococcal or streptococcal disease with potential for toxin production (eg, severe sinusitis, pneumonia, cellulitis), or evidence of an alternative diagnosis for their presentation.

Control subjects were defined as patients who had a diagnosis of KD but who were never admitted to the ICU. Three control subjects were chosen for each case patient and matched to the case by date of admission (±3 weeks). Date of admission was chosen as the matching factor to control for the possibility of variations in circulating strains of a potential "Kawasaki" infectious agent. Medical charts of case patients and control subjects were reviewed by using a standardized form to collect demographic data, clinical information, and laboratory test results. Day 1 of illness was defined as the first day of fever. Intravenous globulin (IVIG)-refractory disease was defined as persistence or recrudescence of fever ≥48 hours after completion of IVIG infusion. For patients who had echocardiograms performed before the institution of routine calculation of z scores, a pediatric cardiologist retrospectively calculated a z score on the basis of coronary artery diameter measurements that were obtained at the time of the original study.

Two-tailed Student's t test was used to test for significant differences in the means of continuous variables. Wilcoxon rank-sum test was used for comparing medians in skewed continuous variables. Proportions were compared using Fisher's exact test. Analyses were conducted by using SAS 9.1.3 (SAS Institute, Inc, Cary, NC). Use of clinical data was approved by the Colorado Multiple Institutional Review Board.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Between January 1995 and December 2007, a total of 423 patients were admitted with a discharge diagnosis of KD. Eighteen (4.3%) of these patients were admitted to the ICU sometime during their hospitalization. Fourteen of these patients met criteria for inclusion in the study. Three patients were excluded because they were admitted to the ICU on a subsequent admission that occurred after their initial diagnosis and treatment for KD. One of these patients was admitted to the ICU after an endomyocardial biopsy, and 2 patients were admitted to the ICU with myocardial infarctions within 1 month of their initial discharge. A fourth patient was excluded because subsequently a diagnosis of juvenile rheumatoid arthritis was made. This diagnosis was based on chart review, normal echocardiograms, rheumatology consultation, and response to steroids.

All 14 patients who were admitted to the ICU were initially evaluated by a board-certified pediatric emergency department physician at our institution. Ten (71%) of these 14 patients were directly admitted to the ICU. The 4 remaining patients were admitted initially to the floor and then transferred to the ICU as a result of deteriorating clinical status. Two of these 4 patients had KD as a leading admitting diagnosis. The other 2 patients had leading diagnoses of viral pneumonitis and severe abdominal pain, respectively. The percentage of patients who had KD and were admitted to the ICU ranged from 0% to 10% per year and did not significantly increase or decrease during the course of the 12-year study.

The demographic characteristics of the case patients and control subjects are shown in Table 1. There were no differences in age between groups even when stratified according to ages of <1 or >6 years.


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  		TABLE 1 Demographics of ICU and Control Patients

 
The clinical characteristics of the case patients and control subjects at time of presentation to the hospital are shown in Table 2. Patients who were admitted to the ICU presented a median of 2.5 days earlier in the course of their illness than control patients with KD (P = .01). The majority of ICU and control patients had complete KD, at both time of admission and time of diagnosis. There was no significant difference noted in individual clinical features at time of presentation (eg, rash, lymphadenopathy, conjunctivitis) between case patients and control subjects; however, ICU patients (29%) were less likely to have an admitting diagnosis of KD compared with control subjects (90%; P < .0001). Eleven (78%) of the 14 patients were admitted to the ICU secondary to hypotension; 10 of these 11 patients required ionotropic support. These patients had a presumptive diagnosis of either toxic shock or septic shock. Two patients were admitted to the ICU because of altered mental status, apnea, and CSF pleocytosis with meningitis. One patient was admitted to the ICU because of a gastrointestinal bleed presumably as a result of mesenteric vasculitis. Patients who were admitted to the ICU were significantly more likely to have fluid-refractory hypotension or gallop (P < .05).


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  		TABLE 2 Clinical Characteristics at Presentation

 
Laboratory values for ICU patients and control subjects are shown in Table 3. At the time of presentation, patients who were admitted to the ICU had a significantly greater percentage of band counts (P < .001), lower platelet counts (P = .001), and lower serum albumin levels (P = .02). In addition, ICU patients had C-reactive protein (CRP) levels that were on average more than twice those of control patients (P < .001). These laboratory values remained significant when looked at over the entire course of the hospital admission. Because of the small number of case patients in our data set, we did not have enough power to conduct a highly informative multivariate analysis. Nevertheless, a binary logistic regression analysis showed that a high percentage of band count and low serum albumin levels were independently correlated with a higher likelihood of admission to the ICU (data not shown). Six (43%) of the ICU patients and 3 (7%) of the control patients had a lumbar puncture performed as part of their initial workup because of concerns for meningitis. Of these, 5 (83%) of the 6 ICU patients and 1 (33%) of the 3 control patients who had a lumbar puncture performed had evidence of CSF pleocytosis (P = .13). On admission, 10 (71%) of the 14 ICU patients had hyponatremia (sodium < 135 mmol/L); 6 (43%) had metabolic acidosis (bicarbonate < 18 mmol/L); 5 (36%) had evidence of acute renal insufficiency with a creatinine level of >1.0 mg/dL, with 1 patient requiring renal dialysis; and 6 (43%) had evidence of coagulopathy. Unfortunately, these laboratory tests were not performed on the majority of the control patients; therefore, a comparison for significance could not be made.


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  		TABLE 3 Laboratory Values of Patients With KD

 
The clinical outcomes of ICU patients versus control patients are shown in Tables 4 and 5. The median length of stay was 5 days longer for ICU patients compared with control subjects (P < .001). Patients who were admitted to the ICU were treated with IVIG and high-dose aspirin a median of 2 days later than control subjects from time of their admission to the hospital (P = .002). Nine (64%) of the 14 ICU patients and 2 (5%) of the 42 control patients had IVIG-refractory disease and required a second therapeutic intervention (P < .001), consisting of a second dose of IVIG, infliximab, and/or steroids.


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  		TABLE 4 Clinical Outcomes of Patients With KD

 

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  		TABLE 5 Echocardiogram Results of Patients With KD

 
All patients had a minimum of 3 echocardiograms performed. The mean ejection fraction of the patients who were admitted to the ICU was 67% (range: 58%–75%; normal: >55%). Only 3 patients, however, had measurements obtained before the administration of IVIG. On qualitative reading of the echocardiogram by a pediatric cardiologist, coronary artery abnormalities (dilatation, ectasia, or aneurysm) were noted on 6 (43%) of 14 ICU patients and 8 (19%) of 42 control patients (P = .09); 4 (29%) of the 14 ICU patients compared with 3 (7%) of the 42 control patients had coronary artery aneurysms (P = .06; Table 5). On quantitative analysis, 7 (50%) of the ICU patients and 19 (45%) of the control patients had coronary artery z scores ≥2.0 (P = .5). For patients who had coronary artery involvement, there was a trend toward patients who were admitted to the ICU to have higher z scores, but this did not reach statistical significance (Table 5).


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
Because there is no diagnostic test or pathognomonic clinical feature of KD, clinicians must maintain a high index of suspicion for KD in febrile patients who present with known clinical features of KD. Diagnosis and treatment of patients with KD depends on an awareness of the full spectrum of the disease presentation. It is now becoming recognized that a large number of patients with KD present without fulfilling full clinical criteria (ie, incomplete KD), and up to 20% of patients who are treated for KD have incomplete cases.1–4 We previously reported that delay in diagnosis was primarily related to a dispersion of symptoms over a longer period of time.5 Several researchers have noted that febrile infants who are younger than 6 months and have KD often present with incomplete criteria and are delayed in receiving a diagnosis because of physicians' failing to consider the diagnosis in this group of patients.5–8

Several authors have described isolated cases of infants and children who had features of toxic shock syndrome and ultimately had a diagnosis of KD.9–11 Here we report a case-control study of a series of patients who had KD and were admitted to the ICU. This report adds to the expanding spectrum of clinical presentations of children with KD. During a 12-year period, 14 patients with KD at our institution were admitted to the ICU primarily because of hypotension and shock. Despite the fact that the majority of these patients met clinical criteria for KD, KD was not the leading diagnosis in these patients, presumably because of the failure to consider KD in patients who present with hypotension that requires ionotropic support and admission to the ICU. This led to a delay in diagnosis and treatment from their time of presentation to the hospital compared with patients who were not admitted to the ICU.

The cause of severe hypotension in patients with KD is unknown. It is likely multifactorial, and possible explanations include vasculitis with ongoing capillary leak, myocardial dysfunction, and cytokine dysregulation.

Recently, there has been considerable effort and interest in trying to define predictors for IVIG-refractory disease at initial presentation in patients with KD.12–15 We found that two thirds of the patients who had KD and were admitted to the ICU had IVIG-refractory disease compared with only 5% of control patients, indicating that admission to the ICU may be an independent predictor of IVIG-refractory disease.

Similar to studies that examined predictors of IVIG-resistant disease, patients who were admitted to the ICU (our "high-risk" group) were more likely to have a very elevated CRP level (double that of control patients) and lower platelet counts. In contrast to other studies, ICU patients had a higher percentage of band count and lower serum albumin levels than control subjects but did not have any significant difference in other hepatic function tests. It is interesting that age was not associated with ICU admission. Female gender, however, was strongly associated with ICU admission. KD is more commonly a disease of males,1 but female gender has not previously been reported to be associated with more severe disease. The reason for this finding is unclear but merits additional investigation.

As demonstrated by other researchers,16,17 our data highlight the need for quantitative analysis of coronary artery disease (z scores) in children with KD, because we found a substantial discrepancy between qualitative and quantitative readings of echocardiograms. We found no difference in the percentage of children who had KD and had coronary artery involvement between those who were admitted to the ICU versus the floor; however, for children who had coronary artery disease, there seemed to be a trend toward those who were admitted to the ICU to have more severe coronary artery involvement/dilation compared with those who were admitted to the floor. Possibly because of our small numbers, this trend did not reach statistical significance. If in fact more severe coronary artery involvement in patients who have KD and are admitted to the ICU is shown by other researchers, then the reasons for having more severe coronary involvement could be related to a more fulminant disease presentation, higher degree of inflammation present (as evidenced by markedly higher CRP levels), and/or a greater degree of myocarditis as evidenced by their presentation in shock. This finding is of importance because these children may be at increased risk for more serious cardiac complications, and diagnosing and treating them promptly may aid in decreasing this risk.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
We present the first case-control study in the English literature of patients who had KD and presented severely ill in shock and required admission to the ICU. These patients frequently received a misdiagnosis because of failure to appreciate the full spectrum of disease severity that is seen in patients with KD. These patients were often mistaken for having toxic or septic shock, leading to a delay in treatment with IVIG. Patients who have KD and are admitted to the ICU are at increased risk for IVIG-refractory disease and may be at risk for development of more severe coronary artery disease.


   ACKNOWLEDGMENTS
 
We thank Dr James K. Todd for statistical assistance.


   FOOTNOTES
 
Accepted Jul 3, 2008.

Address correspondence to Samuel R. Dominguez, MD, PhD, Children's Hospital, Section of Pediatric Infectious Diseases, 13123 E 16th Ave, B055, Aurora, CO 80045. E-mail: samuel.dominguez{at}uchsc.edu

The authors have indicated they have no financial relationships relevant to this article to disclose.


What's Known on This Subject

Isolated reports of patients who had KD that was confused with toxic shock and were admitted to the ICU were identified in the literature.

 

What This Study Adds

To our knowledge, this is the first case-control study of a subgroup of patients who had KD and were quite ill with signs of poor perfusion and hypotension and were admitted to the ICU.

 


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

  1. Burns JC, Glode MP. Kawasaki syndrome. Lancet. 2004;364 (9433):533 –544[CrossRef][ISI][Medline]
  2. Newburger JW, Takahashi M, Gerber MA, et al. Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association [published correction appears in Pediatrics. 2005;115(4):1118]. Pediatrics. 2004;114 (6):1708 –1733[Abstract/Free Full Text]
  3. Yanagawa H, Nakamura Y, Yashiro M, et al. Incidence survey of Kawasaki disease in 1997 and 1998 in Japan. Pediatrics. 2001;107 (3). Available at: www.pediatrics.org/cgi/content/full/107/3/e33
  4. Yanagawa H, Nakamura Y, Yashiro M, et al. Results of the nationwide epidemiologic survey of Kawasaki disease in 1995 and 1996 in Japan. Pediatrics. 1998;102 (6). Available at: www.pediatrics.org/cgi/content/full/102/6/e65
  5. Anderson MS, Todd JK, Glode MP. Delayed diagnosis of Kawasaki syndrome: an analysis of the problem. Pediatrics. 2005;115 (4). Available at: www.pediatrics.org/cgi/content/full/115/4/e428
  6. Rosenfeld EA, Corydon KE, Shulman ST. Kawasaki disease in infants less than one year of age. J Pediatr. 1995;126 (4):524 –529[CrossRef][ISI][Medline]
  7. Chang FY, Hwang B, Chen SJ, Lee PC, Meng CC, Lu JH. Characteristics of Kawasaki disease in infants younger than six months of age. Pediatr Infect Dis J. 2006;25 (3):241 –244[CrossRef][ISI][Medline]
  8. Minich LL, Sleeper LA, Atz AM, et al. Delayed diagnosis of Kawasaki disease: what are the risk factors? Pediatrics. 2007;120 (6). Available at: www.pediatrics.org/cgi/content/full/120/6/e1434
  9. Davies HD, Kirk V, Jadavji T, Kotzin BL. Simultaneous presentation of Kawasaki disease and toxic shock syndrome in an adolescent male. Pediatr Infect Dis J. 1996;15 (12):1136 –1138[CrossRef][ISI][Medline]
  10. Gamillscheg A, Zobel G, Karpf EF, et al. Atypical presentation of Kawasaki disease in an infant. Pediatr Cardiol. 1993;14 (4):223 –226[CrossRef][ISI][Medline]
  11. Chan L, Chinnock B. Clinicopathological conference: multisystem failure in a child. Acad Emerg Med. 2000;7 (2):169 –173[CrossRef][ISI][Medline]
  12. Egami K, Muta H, Ishii M, et al. Prediction of resistance to intravenous immunoglobulin treatment in patients with Kawasaki disease. J Pediatr. 2006;149 (2):237 –240[CrossRef][ISI][Medline]
  13. Kobayashi T, Inoue Y, Takeuchi K, et al. Prediction of intravenous immunoglobulin unresponsiveness in patients with Kawasaki disease. Circulation. 2006;113 (22):2606 –2612[CrossRef][ISI][Medline]
  14. Sano T, Kurotobi S, Matsuzaki K, et al. Prediction of non-responsiveness to standard high-dose gamma-globulin therapy in patients with acute Kawasaki disease before starting initial treatment. Eur J Pediatr. 2007;166 (2):131 –137[CrossRef][ISI][Medline]
  15. Uehara R, Belay ED, Maddox RA, et al. Analysis of potential risk factors associated with nonresponse to initial intravenous immunoglobulin treatment among Kawasaki disease patients in Japan. Pediatr Infect Dis J. 2008;27 (2):155 –160[ISI][Medline]
  16. de Zorzi A, Colan SD, Gauvreau K, Baker AL, Sundel RP, Newburger JW. Coronary artery dimensions may be misclassified as normal in Kawasaki disease. J Pediatr. 1998;133 (2):254 –258[CrossRef][ISI][Medline]
  17. Kurotobi S, Nagai T, Kawakami N, Sano T. Coronary diameter in normal infants, children and patients with Kawasaki disease. Pediatr Int. 2002;44 (1):1 –4[CrossRef][ISI][Medline]
PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics




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