Kawasaki disease: Are we missing the diagnosis
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《美国医学杂志》
Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India
Abstract
We report 6 cases of Kawasaki disease (KD) diagnosed over a period of one year and review of all the cases reported from India. The diagnosis of KD was based on clinical criteria The mean age of patients was 6.83 years and mean duration of symptoms before diagnosis was 7.5 days. Apart from classical clinical features, elevated transaminases and blood urea along with free fluid in abdomen was present in one case each. Two patients had dilated coronaries that returned to normal on follow up. One patient developed headache and neck stiffness following treatment with intravenous gamma globulins. The outcome was excellent in all the cases.
Keywords: Kawasaki disease; Vasculitis; IVIgG
Thirty-six-years ago since Tomi Saku Kawasaki penned the first description of quixotic illness that he called muco- cutaneous lymph node syndrome (Kawasaki syndrome), this illness has been described in every country of the world.[1] Although Kawasaki Disease (KD) has been reported from all over the world, Asia has reported a higher incidence in comparison to other continents. Despite a high Asian incidence of KD, there is a paucity of reports from India. Only 34 cases from India have been reported in the Pediatric literature over the last 25 years.[2] This number of reported cases in one of the most populated countries of the world suggests gross under-diagnosis and or under-reporting/misdiagnosis as other similar illnesses. There could be more number of cases than reported though the reasons for under-reporting could be many. Here are reported 6 cases of KD diagnosed over a period of one year at our Institution. The aim of report is to describe atypical findings in these cases and to highlight the possibility of missing the diagnosis of KD.
Material and Methods
Clinical details of all the cases diagnosed as KD over one year from September 2003 to August 2004 were retrieved. Details including clinical presentation, investigations and treatment were recorded. Their follow up was recorded from case records maintained in Pediatric Rheumatology Clinic. The criteria for diagnosis of classic KD included: fever for at least five days and 4 of the following and lack of another known disease: (i) bilateral conjunctiva congestion, (ii) changes of the mucous membrane of URT (Upper respiratory tract), congested pharynx, congested fissured lips; strawberry tongue, (iii) polymorphous rash, (iv) changes of the extremities; peripheral edema and (v) unilateral lymphadenopathy.[3]
Results
There were total 6 patients of KD diagnosed from September 2003 to August 2004 at the All India Institute of Medical Sciences. All cases fulfilled case definition of classical KD. The authors could not find any case with incomplete KD. Age varied from 2 years to 12 years, mean age being 6.83 years. There were 4 boys and 2 girls. Fever was present in all, with mean duration of fever being 7.5 days; mean duration of illness was 7.5 days with a range 2 to 12 days. All patients had eye lesions and lymphadenopathy; mucosal changes of oral cavity were present in 4 and skin changes in 2. Unusual symptoms like cough, joint pain, decreased oral intake and oliguria were present in one patient each table1. One patient was suffering from mild persistent asthma and was getting inhaled budesonide for past 2 years.
Laboratory work up revealed hemoglobin between 11.5 to 12.5 g/ dL in all the patients. Total leukocyte count was elevated in 2 patients and was predominantly polymorphs. Erythrocyte sedimentation rate (ESR) was universally elevated in all. Mean platelet count in the first week of illness was 3.5 X 105/ mm3 with range of 1.5 to 4.6 X 105/mm3. Platelet counts in the second week of illness were less than 4.5 X 105/ mm3 in two patients and between 4.5 - 7.5 X 105/ mm3 in 4 patients. Abnormal urine examination in form of traces of protein and 8-10 pus cells per high power field were present in one patient. Her blood urea was 72 mg/dL at the time of admission and returned to 20 mg/dL by 5th day. Ultrasonography of her abdomen was within normal limits except minimal free fluid that also resolved after 4 days. One patient had elevated transaminases (SGOT 240 IU/L and SGPT 168 IU/ L). These returned to less than 40 IU/L by end of one week table1.
Echocardiography was performed in all the patients during acute stage and after 6-8 weeks. Two patients had abnormal echocardiography findings in the form of dilatation of left coronary artery. Angiography was performed in them after 4 weeks and were normal. Echocardiography on follow-up was within normal limit in both the patients. All the patients received intravenous immunoglobulin (IVIG) 2gm/kg (total dose) and high dose aspirin 80 mg/kg initially till they became afebrile. Subsequently they received 5 mg/kg/day of aspirin till their platelet counts were high. One patient who received full dose of gamma globulin in 2 days, on the 10th day of illness developed headache and vomiting with neck stiffness. She was treated with paracetamol and intravenous fluids. Her symptoms subsided within 2 days. Four patients became afebrile in 24 hours. Two patients who had liver and renal dysfunction, each of them became afebrile after 72 hours. All 6 patients are in regular follow up at Pediatric Rheumatology Clinic. None is having chronic problem except one who had asthma. Her asthma is well controlled with inhaled corticosteroids.
Discussion
KD is a self-limiting childhood illness, occurring predominantly in age <5 years.[3],[4] It is more common in males (M: F1.5:1).[3], [4] Incidence varies from 120-150/10,000 children < 5 years age group being highest in Japan.[5] The condition was first reported by Kawasaki in 1961 in Tokyo in a Red Cross Hospital.[1] It was recognized as the new and distinct disease entity in the early 1970's by the Melish and Hicks at the University of Hawaii. [6],[7],[8]
First Indian report was given in 1977 by Taneja et al[9] Since then, around 34 cases have been reported by various authors, majority being stray case reports except 3 reports of case series.[2], [10], [11]
The reasons for such a low number of cases over the last 25 years in a largely populated country could be (i) misdiagnosis: as KD is a disease of preschool children < 5 years age group, a large proportion of these cases may be misdiagnosed as viral exanthema especially measles in young children below 5 years of age, (ii) lack of awareness among primary health givers at the first contact at the community level, (iii) as KD is a self limiting illness majority may not come to health care workers, (iv) KD has neither specific diagnostic clinical feature nor a specific diagnostic test, hence difficult to prove and needs a constellation of clinical features to be present which take long time to appear together and which may not be classical, (v) under reporting in literature.
These factors also seem to be present in the present study patients. Mean duration of illness in the present series is around 7.5 days suggesting delayed referral. These have also been suggested by other Indian authors.[2] Probably KD was not considered in the younger children, where they were diagnosed. Whenever patients were older, KD was considered as possibility as measles becomes less common.
Signs and symptoms evolve over ten days, then gradually resolve spontaneously in most children even without specific therapy but with significant morbidity.[12] Diagnosis is mainly by the constellation of symptoms (Criteria), which are by then not pathognomic. These have been described above in 'Methods'. These may not be present simultaneously and usually appear serially. Because of these obstacles in diagnosis of KD, in recent times concept of incomplete (Atypical KD) has emerged.[13], [14] This term should be used for patients having fever for at least five days with 2 of the classic criteria, lack of another known disease process with laboratory findings consistent with systemic infection.[13], [14]
Reviewing all the 40 cases of KD till now reported in Indian subcontinent including the present 6 cases, around 5 were Atypical KD (12%), remaining 88% being classical KD. Among the diagnostic criteria oral cavity lesions were present in 90% (36/40), lymphadenopathy in 82 % (33/40) and changes in extremities in 65% (26/40).
Laboratory investigations have no important role except for elevated ESR, platelet count and echocardiogram. ESR is elevated throughout the course of illness. Platelet count is typically elevated in 2nd week often exceeding 10,00,000 per cubic ml. Echocardiography is an important investigation that needs to be performed in all the patients at admission. Cardiac involvement occurs in the acute stage and significantly contributes to the long-term morbidity. Large series of studies from Japan and North America have established that coronary artery aneurysm occurs as a sequelae of vasculitis in 20- 25% of untreated children.[14] Other cardiovascular manifestations include myocardial involvement, pericardial involvement and endocardial involvement. Echocardiography is a sensitive and reliable method to detect coronary aneurysm in acute and sub acute stages of syndromes.[15],[16]
The importance of early treatment with intravenous gamma globulins (IVIg) and high dose aspirin cannot be overemphasized. Many double blinded RCT have proved that early treatment with IVIg and high dose aspirin hastens resolution of fever and prevents coronary related morbidity and mortality.[17]-[18] None of the patients developed any cardiac complication in the present series. Two patients had coronary abnormality on echocardiography, but on follow-up after treatment they were normal. The other uncommon findings were: raised transaminases, raised blood urea and free fluid in abdomen in both the patients one of the patient developed headache and neck stiffness while getting IVIg. This is a rare but well known side effect of IVIg infusion.
To conclude KD is an important differential diagnosis for fever, rash and lymphadenopathy in children less than 5 years. It is a self limiting illness. However, because of its long term cardiac morbidity in untreated patients there is need to treat all these patients with IVIg and high dose aspirin early in the course of illness to prevent long term morbidity.
References
1. Kawasaki T. Paediatric acute mucocutaneous lymph node syndrome. Clinical observation of 50 cases. ARERUGI (Jpn J Allergy 1967; 16: 178-222.
2. Khubchandani R, D'Souza S. Kawasaki disease in India. Pediatr Rheumat J 2004; 2 : 162-171.
3. Dajani AS, Taburt K A, Gerber MA et al. Diagnosis and therapy of Kawasaki disease in children. Circulation 1993; 87 : 1776-1780.
4. Kawasaki. T. general review and problems in Kawasaki disease. Jpn Heart J 1995; 36 : 1-12.
5. Burns JC, Kushner HI, Bastain JF, Shike H, Shimizu C, Matsubara T et al. Kawasaki disease : brief history. Pediatrics 2000; 106 : 27.
6. Burns JC, Kushner HI, Bastain JF et al. Kawasaki disease : brief history. Pediatrics 2000; 106 : 27.
7. Melish ME, Hicks RM, Larson E. Mucocutaneous lymph node syndrome in US. Pediatr Res 1974; 8 : 427.
8. Melish ME, Hicks RM, Larson E. Mucocutaneous lymph node syndrome in US. Am J Dis Child 1976; 130 : 599-607.
9. Taneja A, Saxena U. Mucocutaneous lymph node syndrome. Indian Pediatr 1977; 14 : 927-931.
10. Singh S, Kumar L, Trehan A, Marwaha RK. Kawasaki disease in chandigarh. Indian Pediatr 1997; 34 : 822-825.
11. Bhagyraj B, Krishnan U, Farzana F. Kawasaki disease in India. Indian J Pediatr 2003; 70 : 919-922
12. Burns JC, Glode PM. Kawasaki syndrome. Lancet 2004; 364: 533-544.
13. Rawlei AH, Gonzalez F, Gidding SS, Duffy E, Shulman ST. Incomplete Kawasaki disease with coronary artery involvement. J Pediatr 1987; 110 : 409-413.
14. Fukushige J, Takahashi N, Ueda Y, Ueda K. Incidence and clinical features of incomplete kawasakai disease. Acta Pediatr 1994; 83 : 1057-1060
15. Suzuki A, Kamiya T, Kuwahara N. Coronary arterial lesion of Kawasaki disease, cardiac catheterization findings of 1100 cases. Pediatr Cardiol 1996; 7 : 3-9.
16. Akagi T, Kato H, Inoue O, Sato N, Imaura K. Valvular heart disease in Kawasaki syndrome incidence and natural history. Am Heart J 1990; 20 : 366-372.
17. Yoshikawa J, Yanagihara K, Owaki T. Cross sectional echocardiographic diagnosis of coronary artery aneurism in patients of Kawasaki disease. J Am Coll Cardiol 1986; 7 : 355-360.
18. Newbergar JW, Takahashi M, Burns JC. Treatment of Kawasaki syndrome with intravenous immunoglobulin. NEJM 1986; 315 : 341-347(Sridhar MR, Goel Himanshu)
Abstract
We report 6 cases of Kawasaki disease (KD) diagnosed over a period of one year and review of all the cases reported from India. The diagnosis of KD was based on clinical criteria The mean age of patients was 6.83 years and mean duration of symptoms before diagnosis was 7.5 days. Apart from classical clinical features, elevated transaminases and blood urea along with free fluid in abdomen was present in one case each. Two patients had dilated coronaries that returned to normal on follow up. One patient developed headache and neck stiffness following treatment with intravenous gamma globulins. The outcome was excellent in all the cases.
Keywords: Kawasaki disease; Vasculitis; IVIgG
Thirty-six-years ago since Tomi Saku Kawasaki penned the first description of quixotic illness that he called muco- cutaneous lymph node syndrome (Kawasaki syndrome), this illness has been described in every country of the world.[1] Although Kawasaki Disease (KD) has been reported from all over the world, Asia has reported a higher incidence in comparison to other continents. Despite a high Asian incidence of KD, there is a paucity of reports from India. Only 34 cases from India have been reported in the Pediatric literature over the last 25 years.[2] This number of reported cases in one of the most populated countries of the world suggests gross under-diagnosis and or under-reporting/misdiagnosis as other similar illnesses. There could be more number of cases than reported though the reasons for under-reporting could be many. Here are reported 6 cases of KD diagnosed over a period of one year at our Institution. The aim of report is to describe atypical findings in these cases and to highlight the possibility of missing the diagnosis of KD.
Material and Methods
Clinical details of all the cases diagnosed as KD over one year from September 2003 to August 2004 were retrieved. Details including clinical presentation, investigations and treatment were recorded. Their follow up was recorded from case records maintained in Pediatric Rheumatology Clinic. The criteria for diagnosis of classic KD included: fever for at least five days and 4 of the following and lack of another known disease: (i) bilateral conjunctiva congestion, (ii) changes of the mucous membrane of URT (Upper respiratory tract), congested pharynx, congested fissured lips; strawberry tongue, (iii) polymorphous rash, (iv) changes of the extremities; peripheral edema and (v) unilateral lymphadenopathy.[3]
Results
There were total 6 patients of KD diagnosed from September 2003 to August 2004 at the All India Institute of Medical Sciences. All cases fulfilled case definition of classical KD. The authors could not find any case with incomplete KD. Age varied from 2 years to 12 years, mean age being 6.83 years. There were 4 boys and 2 girls. Fever was present in all, with mean duration of fever being 7.5 days; mean duration of illness was 7.5 days with a range 2 to 12 days. All patients had eye lesions and lymphadenopathy; mucosal changes of oral cavity were present in 4 and skin changes in 2. Unusual symptoms like cough, joint pain, decreased oral intake and oliguria were present in one patient each table1. One patient was suffering from mild persistent asthma and was getting inhaled budesonide for past 2 years.
Laboratory work up revealed hemoglobin between 11.5 to 12.5 g/ dL in all the patients. Total leukocyte count was elevated in 2 patients and was predominantly polymorphs. Erythrocyte sedimentation rate (ESR) was universally elevated in all. Mean platelet count in the first week of illness was 3.5 X 105/ mm3 with range of 1.5 to 4.6 X 105/mm3. Platelet counts in the second week of illness were less than 4.5 X 105/ mm3 in two patients and between 4.5 - 7.5 X 105/ mm3 in 4 patients. Abnormal urine examination in form of traces of protein and 8-10 pus cells per high power field were present in one patient. Her blood urea was 72 mg/dL at the time of admission and returned to 20 mg/dL by 5th day. Ultrasonography of her abdomen was within normal limits except minimal free fluid that also resolved after 4 days. One patient had elevated transaminases (SGOT 240 IU/L and SGPT 168 IU/ L). These returned to less than 40 IU/L by end of one week table1.
Echocardiography was performed in all the patients during acute stage and after 6-8 weeks. Two patients had abnormal echocardiography findings in the form of dilatation of left coronary artery. Angiography was performed in them after 4 weeks and were normal. Echocardiography on follow-up was within normal limit in both the patients. All the patients received intravenous immunoglobulin (IVIG) 2gm/kg (total dose) and high dose aspirin 80 mg/kg initially till they became afebrile. Subsequently they received 5 mg/kg/day of aspirin till their platelet counts were high. One patient who received full dose of gamma globulin in 2 days, on the 10th day of illness developed headache and vomiting with neck stiffness. She was treated with paracetamol and intravenous fluids. Her symptoms subsided within 2 days. Four patients became afebrile in 24 hours. Two patients who had liver and renal dysfunction, each of them became afebrile after 72 hours. All 6 patients are in regular follow up at Pediatric Rheumatology Clinic. None is having chronic problem except one who had asthma. Her asthma is well controlled with inhaled corticosteroids.
Discussion
KD is a self-limiting childhood illness, occurring predominantly in age <5 years.[3],[4] It is more common in males (M: F1.5:1).[3], [4] Incidence varies from 120-150/10,000 children < 5 years age group being highest in Japan.[5] The condition was first reported by Kawasaki in 1961 in Tokyo in a Red Cross Hospital.[1] It was recognized as the new and distinct disease entity in the early 1970's by the Melish and Hicks at the University of Hawaii. [6],[7],[8]
First Indian report was given in 1977 by Taneja et al[9] Since then, around 34 cases have been reported by various authors, majority being stray case reports except 3 reports of case series.[2], [10], [11]
The reasons for such a low number of cases over the last 25 years in a largely populated country could be (i) misdiagnosis: as KD is a disease of preschool children < 5 years age group, a large proportion of these cases may be misdiagnosed as viral exanthema especially measles in young children below 5 years of age, (ii) lack of awareness among primary health givers at the first contact at the community level, (iii) as KD is a self limiting illness majority may not come to health care workers, (iv) KD has neither specific diagnostic clinical feature nor a specific diagnostic test, hence difficult to prove and needs a constellation of clinical features to be present which take long time to appear together and which may not be classical, (v) under reporting in literature.
These factors also seem to be present in the present study patients. Mean duration of illness in the present series is around 7.5 days suggesting delayed referral. These have also been suggested by other Indian authors.[2] Probably KD was not considered in the younger children, where they were diagnosed. Whenever patients were older, KD was considered as possibility as measles becomes less common.
Signs and symptoms evolve over ten days, then gradually resolve spontaneously in most children even without specific therapy but with significant morbidity.[12] Diagnosis is mainly by the constellation of symptoms (Criteria), which are by then not pathognomic. These have been described above in 'Methods'. These may not be present simultaneously and usually appear serially. Because of these obstacles in diagnosis of KD, in recent times concept of incomplete (Atypical KD) has emerged.[13], [14] This term should be used for patients having fever for at least five days with 2 of the classic criteria, lack of another known disease process with laboratory findings consistent with systemic infection.[13], [14]
Reviewing all the 40 cases of KD till now reported in Indian subcontinent including the present 6 cases, around 5 were Atypical KD (12%), remaining 88% being classical KD. Among the diagnostic criteria oral cavity lesions were present in 90% (36/40), lymphadenopathy in 82 % (33/40) and changes in extremities in 65% (26/40).
Laboratory investigations have no important role except for elevated ESR, platelet count and echocardiogram. ESR is elevated throughout the course of illness. Platelet count is typically elevated in 2nd week often exceeding 10,00,000 per cubic ml. Echocardiography is an important investigation that needs to be performed in all the patients at admission. Cardiac involvement occurs in the acute stage and significantly contributes to the long-term morbidity. Large series of studies from Japan and North America have established that coronary artery aneurysm occurs as a sequelae of vasculitis in 20- 25% of untreated children.[14] Other cardiovascular manifestations include myocardial involvement, pericardial involvement and endocardial involvement. Echocardiography is a sensitive and reliable method to detect coronary aneurysm in acute and sub acute stages of syndromes.[15],[16]
The importance of early treatment with intravenous gamma globulins (IVIg) and high dose aspirin cannot be overemphasized. Many double blinded RCT have proved that early treatment with IVIg and high dose aspirin hastens resolution of fever and prevents coronary related morbidity and mortality.[17]-[18] None of the patients developed any cardiac complication in the present series. Two patients had coronary abnormality on echocardiography, but on follow-up after treatment they were normal. The other uncommon findings were: raised transaminases, raised blood urea and free fluid in abdomen in both the patients one of the patient developed headache and neck stiffness while getting IVIg. This is a rare but well known side effect of IVIg infusion.
To conclude KD is an important differential diagnosis for fever, rash and lymphadenopathy in children less than 5 years. It is a self limiting illness. However, because of its long term cardiac morbidity in untreated patients there is need to treat all these patients with IVIg and high dose aspirin early in the course of illness to prevent long term morbidity.
References
1. Kawasaki T. Paediatric acute mucocutaneous lymph node syndrome. Clinical observation of 50 cases. ARERUGI (Jpn J Allergy 1967; 16: 178-222.
2. Khubchandani R, D'Souza S. Kawasaki disease in India. Pediatr Rheumat J 2004; 2 : 162-171.
3. Dajani AS, Taburt K A, Gerber MA et al. Diagnosis and therapy of Kawasaki disease in children. Circulation 1993; 87 : 1776-1780.
4. Kawasaki. T. general review and problems in Kawasaki disease. Jpn Heart J 1995; 36 : 1-12.
5. Burns JC, Kushner HI, Bastain JF, Shike H, Shimizu C, Matsubara T et al. Kawasaki disease : brief history. Pediatrics 2000; 106 : 27.
6. Burns JC, Kushner HI, Bastain JF et al. Kawasaki disease : brief history. Pediatrics 2000; 106 : 27.
7. Melish ME, Hicks RM, Larson E. Mucocutaneous lymph node syndrome in US. Pediatr Res 1974; 8 : 427.
8. Melish ME, Hicks RM, Larson E. Mucocutaneous lymph node syndrome in US. Am J Dis Child 1976; 130 : 599-607.
9. Taneja A, Saxena U. Mucocutaneous lymph node syndrome. Indian Pediatr 1977; 14 : 927-931.
10. Singh S, Kumar L, Trehan A, Marwaha RK. Kawasaki disease in chandigarh. Indian Pediatr 1997; 34 : 822-825.
11. Bhagyraj B, Krishnan U, Farzana F. Kawasaki disease in India. Indian J Pediatr 2003; 70 : 919-922
12. Burns JC, Glode PM. Kawasaki syndrome. Lancet 2004; 364: 533-544.
13. Rawlei AH, Gonzalez F, Gidding SS, Duffy E, Shulman ST. Incomplete Kawasaki disease with coronary artery involvement. J Pediatr 1987; 110 : 409-413.
14. Fukushige J, Takahashi N, Ueda Y, Ueda K. Incidence and clinical features of incomplete kawasakai disease. Acta Pediatr 1994; 83 : 1057-1060
15. Suzuki A, Kamiya T, Kuwahara N. Coronary arterial lesion of Kawasaki disease, cardiac catheterization findings of 1100 cases. Pediatr Cardiol 1996; 7 : 3-9.
16. Akagi T, Kato H, Inoue O, Sato N, Imaura K. Valvular heart disease in Kawasaki syndrome incidence and natural history. Am Heart J 1990; 20 : 366-372.
17. Yoshikawa J, Yanagihara K, Owaki T. Cross sectional echocardiographic diagnosis of coronary artery aneurism in patients of Kawasaki disease. J Am Coll Cardiol 1986; 7 : 355-360.
18. Newbergar JW, Takahashi M, Burns JC. Treatment of Kawasaki syndrome with intravenous immunoglobulin. NEJM 1986; 315 : 341-347(Sridhar MR, Goel Himanshu)