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A one-year-old boy with cervical adenopathy and fever
Pediatric Infectious Disease 2012 December Volume 4, Number 4; pp. 183e187
Case Files
A one-year-old boy with cervical adenopathy and fever S. Balasubramaniana,*, Sumanth Amperayanib,d, K. Dhanalakshmib,d, Vijay Viswanathanc Keywords: Adenitis, MSSA, Kawasaki disease
CASE FILES
Dr. Balasubramanian
Dr. Sumanth Amperayani
Kawasaki disease (KD) does not have any specific diagnostic tests as such and as mentioned above, the aforesaid clinical features along with high index of suspicion should lead to the diagnosis. To confirm this however I would like to do certain blood investigations and an Echocardiography. Viral illness (Adenovirus, Cytomegalovirus (CMV) and Epstein Barr virus (EBV)) may present like this along with adenitis but suppuration is an unlikely feature in them. However I would like to wait and watch as the disease process evolves before committing on the diagnosis of prolonged viral illness alone. Coming to suppurative adenitis, it seems to me the most likely possibility, considering the acute nature of the illness and the hectic fever.
This is a 1-year-old male child who was previously well. He was born to parents of non-consanguineous marriage and appropriately immunized. He is admitted to our hospital on the 5th day of fever due to high rise of temperature and irritability along with a swelling in the left cervical region. On examination he has pallor and tender left anterior cervical adenopathy with the upper jugulodigastric nodes measuring 4 5 cm. The nodes are tender and warm but not red. He is irritable and has bulbar conjunctival suffusion. He also has perianal erythema and excoriation. Liver and spleen are not palpable and there are no other palpable lymph nodes of significance. ENT examination is normal. This looks like acute suppurative adenitis of the left jugulodigastric nodes. Would you like to consider any other differential diagnosis sir?
Dr. S. Balasubramanian With his bulbar conjunctival suffusion, fever of 5 days duration and cervical adenopathy and other features like perianal excoriation, irritability and bulbar conjunctivitis (non-purulent), I would like to consider Kawasaki disease, viral illness and as you have pointed out, acute suppurative adenitis.
Dr. Sumanth Amperayani How do you differentiate these on clinical grounds sir?
Dr. Sumanth Amperayani The investigation reports for the kid and are as follows: a total count of 24100/mm3 and Hb of only 9.7 gm%, with polymorphonuclear leucocytosis and a platelet count of 8.5 lakhs. ESR is 84 mm in the 1st hour and CRP is 94. Echo is normal. Dr. Dhanalakshmi e how do you interpret these investigation reports.1,2
Dr. Dhanalakshmi All investigations put together give me an impression of an inflammation rather than infection going on in the body. High platelet counts with leucocytosis suggests non-infective inflammation rather a simple bacterial infection. I would like to consider ordering further investigations like urine
a Senior Consultant Pediatrician, bSenior Registrar, Kanchi Kamakoti Childs Trust Hospital and the Childs Trust Medical Research Foundation (CTMRF), 12-A, Nageswara Road, Nungambakkam, Chennai 600034, cConsultant Pediatric Rheumatologist, MGMs New Bombay Hospital, Vashi Dr Yewale's Multispecialty Centre, Vashi, Navi Mumbai 400703, India. * Corresponding author. Tel.: þ91 (0) 44 42001800x139, email: [email protected] Received: 27.11.2012; Accepted: 24.12.2012; Available online: 7.1.2013 d Tel.: þ91 (0) 44 42001800x139. Copyright Ó 2013, Indian Academy of Pediatrics, Infectious Disease Chapter. All rights reserved.
http://dx.doi.org/10.1016/j.pid.2012.12.011
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Balasubramanian et al.
microscopy, ALT and AST to look for evidence of inflammation elsewhere (sterile pyuria and elevated transaminases) and of course a blood culture specifically for Streptococcus and Staph. aureus.
on Aspirin 30 mg/kg/day. Though the size of the adenitis is decreasing the fever is still hectic and the same as before. What can be done further and should we consider any other differentials sir?
Dr. Sumanth Amperayani
Dr. S. Balasubramanian
LFT is normal except for mildly elevated lever enzymes (AST 84 and ALT 116) with urine routine showing 10e15 pus cells per high power field. USG abdomen is suggestive of hydrops of gall bladder.
We can give a 2nd dose of IVIg and at this juncture. I would like to consider doing a bone marrow aspiration cytology and culture and workup for viral infections like EBV and CMV and also a repeat CBC, ESR and CRP again which will tell us whether we are on the right track.
Dr. Dhanalakshmi What would be the appropriate management of this case at this juncture sir?
Dr. S. Balasubramanian At this point of time I would like to consider Kawasaki disease. (The epidemiological case definition of KD has been elucidated in Table 1). At the same time infection may not be ruled out conclusively. I would like to start the child on IVIg and I would also look for other signs of Kawasaki disease like BCG scar changes etc. As a learning point I reiterate the fact that erythema and induration at the BCG scar site suggests persisting inflammation in Kawasaki and may occur late and perianal excoriation suggests active disease and occurs pretty early. We can start IVIg 2 g/kg over 24 h and Aspirin 30 or 60 mg/kg/day.
Dr. Dhanalakshmi The case has now evolved sir. This is day 9 of fever. After one dose of IVIg fever is still persisting and the kid is also Table 1 Case definition of Kawasaki disease. Fever persisting at least 5 days Presence of at least 4 principal features: Changes in extremities Acute: erythema of palms, soles; edema of hands, feet Subacute: periungual peeling of fingers, toes in weeks 2 and 3 Polymorphous exanthem Bilateral bulbar conjunctival injection without exudate Changes in lips and oral cavity: erythema, lips cracking, strawberry tongue, diffuse injection of oral and pharyngeal mucosae Cervical lymphadenopathy (1.5-cm diameter), usually unilateral
Dr. Sumanth Amperayani Repeat counts are the same sir. TC is 24,700 with a platelet count of 7.6 lakhs, however the ESR and CRP are now decreased. ESR is 42 mm in 1st hour and CRP is 42. EBV VCA IgM has turned out to be positive and CMV IgM is negative. Blood culture is negative. But the child’s clinical status is unchanged and he continues to have hectic fever. Perianal excoriation is settling. But adenitis has increased in size. Kawasaki disease as we well know may be auto immune related or may be due to the super antigens from infections. The hypothesis that Kawasaki disease is related to a bacterial superantigenic toxin has been suggested because of the reported selective expansion of Vb2 and Vb8 T-cell receptor families, but this theory remains controversial.3 Recent studies throw light on other hypotheses too. The immune response in Kawasaki disease is oligoclonal (antigen driven, i.e., similar to a response to a conventional antigen) rather than polyclonal (as found typically in super antigen-driven responses), and immunoglobulin A (IgA) plasma cells play a central role.4 It also is possible that Kawasaki disease results from an immunologic response that is triggered by any of several different microbial agents. Support for this hypothesis includes documented infection by different microorganisms in different individual cases, failure to detect a single microbiological or environmental agent after almost 3 decades of study, and analogies to other syndromes caused by multiple agents (eg, aseptic meningitis). This hypothesis is somewhat difficult to reconcile with the distinctive clinical/laboratory picture of Kawasaki disease and with its epidemiological features. Keeping this in mind, could all this be explained by infection alone sir?
Dr. S. Balasubramanian Unlikely that everything is occurring only due to infection. The suppurative adenitis itself is well explained as an
A one-year-old boy with cervical adenopathy and fever
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associated feature of Kawasaki disease. Lymphadenopathy, an early finding in patients with Kawasaki disease, usually regresses after IVIg. Pathological findings in lymph nodes include thrombotic arteriolitis and severe lymphadenitis with necrosis.5 Lymph node biopsies performed in the first week of the illness in earlier reported studies revealed abnormal hyperplasia of the endothelium of the postcapillary venule and hyperplasia of reticular cells around the postcapillary venule.6 I would like to go ahead and do a lymph node biopsy. Is the bone marrow culture growing anything?
Dr. S. Balasubramanian
Dr. Dhanalakshmi
Dr. Sumanth Amperayani
Now it is day 14 and blood and bone marrow cultures are sterile sir. When the surgeons wanted to do a biopsy, they found a large collection of pus in the site and they ended doing an incision and drainage. I got a call from the operation theater that they are sending the pus for Gram stain and culture and sensitivity and asking me if we wanted any other tests to be done. I suggested that that the pus sample be sent for AFB staining and culture and also. Was I right in doing so sir?
Repeat Echocardiography has shown ectasia of the right coronary artery confirming the diagnosis of Kawasaki disease. Now, what is the final diagnosis sir?
Dr. S. Balasubramanian
Dr. Sumanth Amperayani
You are absolutely right in ordering that because TB is one disease that can masquerade any known clinical condition and that too in the Indian context it is perfectly justified.
We know that Kawasaki disease is an inflammation and not an infection. But, could infections be associated with Kawasaki disease sir?
Dr. Sumanth Amperayani
Dr. S. Balasubramanian
It is day 15 now and the pus for AFB stain is negative sir and Gram stain is showing organisms in clusters. What antibiotics would you consider pending cultures sir?
Yes. In a study in 2005, concurrent infections have been observed in 33% of children with typical Kawasaki Disease. These children had > or ¼ 1 confirmed infection at KD diagnosis.9 Although Kawasaki disease (KD) often presents with sterile pyuria, bacterial pyuria (urinary tract infection [UTI]) occasionally occurs. Pyuria was not always sterile in patients with KD. Although there is no difference in clinical phenotype or coronary outcome in KD patients with or without UTI, it is suggested that UTI should be considered and evaluated in KD patients with pyuria, a positive nitrite test or a positive result of urine culture. If UTI is definitively diagnosed, the patient should be treated for a UTI as well as for KD and complete post-UTI work-up is recommended.10 In a similar study even concurrent Adenoviral infection was found in Kawasaki disease though not an association or cause and effect proved between the two.11 It is interesting to note that the ubiquitous Mycoplasma is associated with Kawasaki disease. There are several case reports linking Mycoplasma
Dr. S. Balasubramanian The right choice now would be to start on Vancomycin as unless otherwise proven all severe infections due to staphylococci community acquired are to be considered to be due to community acquired MRSA. We can de-escalate the antibiotics after the culture results come if needed.7
Dr. Dhanalakshmi It is day 17 of fever and the culture report shows MSSA sir. What about stopping Vancomycin and starting the kid on Cloxacillin monotherapy? What about continuing Aspirin and the follow up of the case sir?
We will start the kid on Cloxacillin 100 mg/kg/day for a total of 10 days and will continue to give Aspirin at 30 mg/kg/day for another 2 weeks. For MSSA, Cloxacillin is superior to Vancomycin. After 2 weeks we will repeat Echocardiography, CBC, ESR and CRP. If all the acute phase reactants have normalized and the child is also clinically well with Echo being normal, then we will decrease the Aspirin to 5 mg/kg/day and then follow up according to American Heart Association consensus guidelines.8
Dr. S. Balasubramanian Kawasaki disease with acute left staphylococcal suppurative cervical adenitis.
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pneumoniae to Kawasaki disease as a possible trigger. This is perhaps due to a super antigen or is mediated by some other mechanism. Accurate and timely testing for Mycoplasma infections is difficult and has its limitations. Despite this, Mycoplasma pneumoniae should be considered in the differential and workup for Kawasaki disease.12 The dilemma in this case was to start antibiotics or not. In this case, we started antibiotics after pus was obtained on incision. In retrospect we should have given antibiotics earlier. Also in this case, the “failure” to respond to the first dose of IVIg may be because the infection was not controlled and not due to a failure to respond to the 1st dose of IVIg per se. It is 2 weeks after draining pus and the infant has completely recovered. We plan to follow the infant’s status with an ECHO at 6 weeks.
Balasubramanian et al.
5.
6.
PRACTICE PEARLS FROM THE EXPERT Dr Vijay Viswanathan (Pediatric Rheumatologist). 7. Kawasaki disease: a few clinically relevant points reviewed. 1. Tomisaku Kawasaki published the first Englishlanguage report of 50 patients with Kawasaki disease (KD) in 1974. Since that time, KD has become the leading cause of acquired heart disease among children in North America and Japan and cases in India seem to be on the rise mainly due to better awareness. 2. The causal agent of Kawasaki disease (KD) remains unknown after more than 40 years of intensive research. Superantigen toxins, role of IgA plasma cells in a genetically susceptible host have been postulated. 3. More recently analyses of the three major KD epidemics in Japan, major non-epidemic inter annual fluctuations of KD cases in Japan and San Diego, and the seasonal variation of KD in Japan, Hawaii, and San Diego, reveals a consistent pattern wherein KD cases are often linked to large-scale wind currents originating in central Asia and traversing the north Pacific. Results suggest that the environmental trigger for KD could be wind-borne.13 4. The classic diagnosis of Kawasaki disease has been based on the presence of 5 days of fever and 4 of the 5 principal clinical features. Typically, all of the clinical features are not present at a single point in time, and watchful waiting is sometimes necessary before a diagnosis can be made. In the presence of 4 principal criteria, the diagnosis of Kawasaki disease can be made on day 4 of illness. Kawasaki disease
8.
9.
should be considered in the differential diagnosis of a young child with unexplained fever for 5 days that is associated with any of the principal clinical features of this disease. The term “incomplete” may be preferable to “atypical” because these patients lack sufficient clinical signs of the disease to fulfill the classic criteria; they do not demonstrate atypical clinical features. The phrase “atypical Kawasaki disease” should be reserved for patients who have a problem, such as renal impairment, that generally is not seen in Kawasaki disease. Incomplete Kawasaki disease should be considered in all children with unexplained fever for 5 days associated with 2 or 3 of the principal clinical features of Kawasaki disease Because young infants may present with fever and few, if any, principal clinical features (and a high chance of coronary changes), echocardiography should be considered in any infant aged 6 months with fever of 7 days’ duration, laboratory evidence of systemic inflammation, no other explanation for the febrile illness. The importance of BCG reactivation, gall bladder hydrops, sterile pyuria (documented pyuria plus a negative urine culture) cannot be overemphasized when dealing with incomplete cases. Also hypoalbuminemia, transaminitis along with thrombocytosis, neutrophilic leucocytosis and anemia add to the index of suspicion for KD. Occasionally thrombocytopenia can be seen and these are the cases who need to be followed up closely for complications. Coronary artery aneurysms or ectasia develop in 15%e25% of untreated children. The Japanese Ministry of Health criteria classify coronary arteries as abnormal if the internal lumen diameter is 3 mm in children 5 years old or 4 mm in children 5 years old; if the internal diameter of a segment measures 1.5 times that of an adjacent segment; or if the coronary lumen is clearly irregular. A Z score should always be sought from the cardiologist to document coronary dilatation. Treatment of KD with aspirin alone has never been subject to a randomized controlled trial, although aspirin versus aspirin plus IVIg has been studied. Meta-analysis comparing moderate anti-inflammatory doses of aspirin (30e50 mg/kg/day)14 with IVIg versus high dose aspirin (80e120 mg/kg/day) with IVIg found no significant difference in the incidence of CAA between the groups. Literature mentions a wide range as far as the anti-inflammatory dose of aspirin is concerned (30e100 mg/kg/d). Asian children are believed to experience more aspirin related
A one-year-old boy with cervical adenopathy and fever
toxicity hence 30e50 mg/kg/day is used in the Asian setting. To conclude, with current level of evidence, in a high risk clinical setting eg, GI bleeding secondary to vasculitis, hematemesis, a lower antiinflammatory dose (30e50 mg/kg can be used) with no difference in CAA risk. Aspirin may be reduced to anti platelet dose 48 h after fever defervesces. 10. Use of IVIg reduces the risk of cardiac involvement to 2%. IVIg resistance is defined as failure of fever to resolve after 36 h since finishing infusion. In these cases, a second IVIg is recommended. Though preferable to give within the first 10 days, in situations with ongoing inflammation, it should be given even after day 10 of illness. 11. Finally with current level of evidence it may be rational to use steroids in a resource poor setting like ours if a second IVIg fails, or access to biologicals (infliximab) not available. Studies have shown better defervescence of fever, normalization of labs with no significant bearing on coronary outcomes.
FUNDING
Case Files
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7.
8.
9.
None.
CONFLICTS OF INTEREST All authors have none to declare.
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REFERENCES 12. 1. Akagi T, Kato H, Inoue O, Sato N. A study on the optimal dose of aspirin therapy in Kawasaki disease e clinical evaluation and arachidonic acid metabolism. Kurume Med J. 1990;37:203e208. 2. Maconochie Ian K. Kawasaki disease Best Practice. Arch Dis Child Educ Pract Ed. 2004;89:ep3eep8. http://dx.doi.org/10. 1136/adc.2004.053728. 3. Leung DY, Giorno RC, Kazemi LV, Flynn PA, Busse JB. Evidence for superantigen involvement in cardiovascular
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14.
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injury due to Kawasaki syndrome. J Immunol. 1995;155: 5018e5021. Rowley AH, Shulman ST, Spike BT, Mask CA, Baker SC. Oligoclonal IgA response in the vascular wall in acute Kawasaki disease. J Immunol. 2001;166:1334e1343. Naoe S, Takahashi K, Masuda H, Tanaka N. Kawasaki disease. With particular emphasis on arterial lesions. Acta Pathol Jpn. 1991;41:785e797. Kawasaki T. Acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the fingers and toes in children [in Japanese]. Arerugi. 1967;16:178. Liu Catherine. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillinresistant Staphylococcus aureus infections in adults and children: executive summary. MRSA treatment guidelines. CID. 2011;52:285e292. 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. Circulation. 2004;110:2747e2771. Benseler SM, McCrindle BW, Silverman ED, Tyrrell PN, Wong J, Yeung RS. Infections and Kawasaki disease: implications for coronary artery outcome. Pediatrics. 2005;116: 760e766. Jan SL, Wu MC, Lin MC, Fu YC, Chan SC, Lin SJ. Pyuria is not always sterile in children with Kawasaki disease. Pediatr Int. 2010;52:113e117. Shike H, Shimizu C, Kanegaye JT, et al. Adenovirus, adenoassociated virus and Kawasaki disease. Pediatr Infect Dis J. 2005;24:1011e1014. Ebrahim M, Gabay M, Rivas-Chacon RF. Evidence of acute mycoplasma infection in a patient with incomplete and atypical Kawasaki disease: a case report. Case Rep Med; 2011: 606920. Rodó X, Ballester J, Cayan D, et al. Association of Kawasaki disease with tropospheric wind patterns. Scientific Reports. 2011;1(152). Brogan PA, Bose A, Burgner D, et al. Kawasaki disease: an evidence based approach to diagnosis, treatment, and proposals for future research. Arch Dis Child. 2002;86:286e290.
Case Files
A one-year-old boy with cervical adenopathy and fever S. Balasubramaniana,*, Sumanth Amperayanib,d, K. Dhanalakshmib,d, Vijay Viswanathanc Keywords: Adenitis, MSSA, Kawasaki disease
CASE FILES
Dr. Balasubramanian
Dr. Sumanth Amperayani
Kawasaki disease (KD) does not have any specific diagnostic tests as such and as mentioned above, the aforesaid clinical features along with high index of suspicion should lead to the diagnosis. To confirm this however I would like to do certain blood investigations and an Echocardiography. Viral illness (Adenovirus, Cytomegalovirus (CMV) and Epstein Barr virus (EBV)) may present like this along with adenitis but suppuration is an unlikely feature in them. However I would like to wait and watch as the disease process evolves before committing on the diagnosis of prolonged viral illness alone. Coming to suppurative adenitis, it seems to me the most likely possibility, considering the acute nature of the illness and the hectic fever.
This is a 1-year-old male child who was previously well. He was born to parents of non-consanguineous marriage and appropriately immunized. He is admitted to our hospital on the 5th day of fever due to high rise of temperature and irritability along with a swelling in the left cervical region. On examination he has pallor and tender left anterior cervical adenopathy with the upper jugulodigastric nodes measuring 4 5 cm. The nodes are tender and warm but not red. He is irritable and has bulbar conjunctival suffusion. He also has perianal erythema and excoriation. Liver and spleen are not palpable and there are no other palpable lymph nodes of significance. ENT examination is normal. This looks like acute suppurative adenitis of the left jugulodigastric nodes. Would you like to consider any other differential diagnosis sir?
Dr. S. Balasubramanian With his bulbar conjunctival suffusion, fever of 5 days duration and cervical adenopathy and other features like perianal excoriation, irritability and bulbar conjunctivitis (non-purulent), I would like to consider Kawasaki disease, viral illness and as you have pointed out, acute suppurative adenitis.
Dr. Sumanth Amperayani How do you differentiate these on clinical grounds sir?
Dr. Sumanth Amperayani The investigation reports for the kid and are as follows: a total count of 24100/mm3 and Hb of only 9.7 gm%, with polymorphonuclear leucocytosis and a platelet count of 8.5 lakhs. ESR is 84 mm in the 1st hour and CRP is 94. Echo is normal. Dr. Dhanalakshmi e how do you interpret these investigation reports.1,2
Dr. Dhanalakshmi All investigations put together give me an impression of an inflammation rather than infection going on in the body. High platelet counts with leucocytosis suggests non-infective inflammation rather a simple bacterial infection. I would like to consider ordering further investigations like urine
a Senior Consultant Pediatrician, bSenior Registrar, Kanchi Kamakoti Childs Trust Hospital and the Childs Trust Medical Research Foundation (CTMRF), 12-A, Nageswara Road, Nungambakkam, Chennai 600034, cConsultant Pediatric Rheumatologist, MGMs New Bombay Hospital, Vashi Dr Yewale's Multispecialty Centre, Vashi, Navi Mumbai 400703, India. * Corresponding author. Tel.: þ91 (0) 44 42001800x139, email: [email protected] Received: 27.11.2012; Accepted: 24.12.2012; Available online: 7.1.2013 d Tel.: þ91 (0) 44 42001800x139. Copyright Ó 2013, Indian Academy of Pediatrics, Infectious Disease Chapter. All rights reserved.
http://dx.doi.org/10.1016/j.pid.2012.12.011
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Balasubramanian et al.
microscopy, ALT and AST to look for evidence of inflammation elsewhere (sterile pyuria and elevated transaminases) and of course a blood culture specifically for Streptococcus and Staph. aureus.
on Aspirin 30 mg/kg/day. Though the size of the adenitis is decreasing the fever is still hectic and the same as before. What can be done further and should we consider any other differentials sir?
Dr. Sumanth Amperayani
Dr. S. Balasubramanian
LFT is normal except for mildly elevated lever enzymes (AST 84 and ALT 116) with urine routine showing 10e15 pus cells per high power field. USG abdomen is suggestive of hydrops of gall bladder.
We can give a 2nd dose of IVIg and at this juncture. I would like to consider doing a bone marrow aspiration cytology and culture and workup for viral infections like EBV and CMV and also a repeat CBC, ESR and CRP again which will tell us whether we are on the right track.
Dr. Dhanalakshmi What would be the appropriate management of this case at this juncture sir?
Dr. S. Balasubramanian At this point of time I would like to consider Kawasaki disease. (The epidemiological case definition of KD has been elucidated in Table 1). At the same time infection may not be ruled out conclusively. I would like to start the child on IVIg and I would also look for other signs of Kawasaki disease like BCG scar changes etc. As a learning point I reiterate the fact that erythema and induration at the BCG scar site suggests persisting inflammation in Kawasaki and may occur late and perianal excoriation suggests active disease and occurs pretty early. We can start IVIg 2 g/kg over 24 h and Aspirin 30 or 60 mg/kg/day.
Dr. Dhanalakshmi The case has now evolved sir. This is day 9 of fever. After one dose of IVIg fever is still persisting and the kid is also Table 1 Case definition of Kawasaki disease. Fever persisting at least 5 days Presence of at least 4 principal features: Changes in extremities Acute: erythema of palms, soles; edema of hands, feet Subacute: periungual peeling of fingers, toes in weeks 2 and 3 Polymorphous exanthem Bilateral bulbar conjunctival injection without exudate Changes in lips and oral cavity: erythema, lips cracking, strawberry tongue, diffuse injection of oral and pharyngeal mucosae Cervical lymphadenopathy (1.5-cm diameter), usually unilateral
Dr. Sumanth Amperayani Repeat counts are the same sir. TC is 24,700 with a platelet count of 7.6 lakhs, however the ESR and CRP are now decreased. ESR is 42 mm in 1st hour and CRP is 42. EBV VCA IgM has turned out to be positive and CMV IgM is negative. Blood culture is negative. But the child’s clinical status is unchanged and he continues to have hectic fever. Perianal excoriation is settling. But adenitis has increased in size. Kawasaki disease as we well know may be auto immune related or may be due to the super antigens from infections. The hypothesis that Kawasaki disease is related to a bacterial superantigenic toxin has been suggested because of the reported selective expansion of Vb2 and Vb8 T-cell receptor families, but this theory remains controversial.3 Recent studies throw light on other hypotheses too. The immune response in Kawasaki disease is oligoclonal (antigen driven, i.e., similar to a response to a conventional antigen) rather than polyclonal (as found typically in super antigen-driven responses), and immunoglobulin A (IgA) plasma cells play a central role.4 It also is possible that Kawasaki disease results from an immunologic response that is triggered by any of several different microbial agents. Support for this hypothesis includes documented infection by different microorganisms in different individual cases, failure to detect a single microbiological or environmental agent after almost 3 decades of study, and analogies to other syndromes caused by multiple agents (eg, aseptic meningitis). This hypothesis is somewhat difficult to reconcile with the distinctive clinical/laboratory picture of Kawasaki disease and with its epidemiological features. Keeping this in mind, could all this be explained by infection alone sir?
Dr. S. Balasubramanian Unlikely that everything is occurring only due to infection. The suppurative adenitis itself is well explained as an
A one-year-old boy with cervical adenopathy and fever
Case Files
185
associated feature of Kawasaki disease. Lymphadenopathy, an early finding in patients with Kawasaki disease, usually regresses after IVIg. Pathological findings in lymph nodes include thrombotic arteriolitis and severe lymphadenitis with necrosis.5 Lymph node biopsies performed in the first week of the illness in earlier reported studies revealed abnormal hyperplasia of the endothelium of the postcapillary venule and hyperplasia of reticular cells around the postcapillary venule.6 I would like to go ahead and do a lymph node biopsy. Is the bone marrow culture growing anything?
Dr. S. Balasubramanian
Dr. Dhanalakshmi
Dr. Sumanth Amperayani
Now it is day 14 and blood and bone marrow cultures are sterile sir. When the surgeons wanted to do a biopsy, they found a large collection of pus in the site and they ended doing an incision and drainage. I got a call from the operation theater that they are sending the pus for Gram stain and culture and sensitivity and asking me if we wanted any other tests to be done. I suggested that that the pus sample be sent for AFB staining and culture and also. Was I right in doing so sir?
Repeat Echocardiography has shown ectasia of the right coronary artery confirming the diagnosis of Kawasaki disease. Now, what is the final diagnosis sir?
Dr. S. Balasubramanian
Dr. Sumanth Amperayani
You are absolutely right in ordering that because TB is one disease that can masquerade any known clinical condition and that too in the Indian context it is perfectly justified.
We know that Kawasaki disease is an inflammation and not an infection. But, could infections be associated with Kawasaki disease sir?
Dr. Sumanth Amperayani
Dr. S. Balasubramanian
It is day 15 now and the pus for AFB stain is negative sir and Gram stain is showing organisms in clusters. What antibiotics would you consider pending cultures sir?
Yes. In a study in 2005, concurrent infections have been observed in 33% of children with typical Kawasaki Disease. These children had > or ¼ 1 confirmed infection at KD diagnosis.9 Although Kawasaki disease (KD) often presents with sterile pyuria, bacterial pyuria (urinary tract infection [UTI]) occasionally occurs. Pyuria was not always sterile in patients with KD. Although there is no difference in clinical phenotype or coronary outcome in KD patients with or without UTI, it is suggested that UTI should be considered and evaluated in KD patients with pyuria, a positive nitrite test or a positive result of urine culture. If UTI is definitively diagnosed, the patient should be treated for a UTI as well as for KD and complete post-UTI work-up is recommended.10 In a similar study even concurrent Adenoviral infection was found in Kawasaki disease though not an association or cause and effect proved between the two.11 It is interesting to note that the ubiquitous Mycoplasma is associated with Kawasaki disease. There are several case reports linking Mycoplasma
Dr. S. Balasubramanian The right choice now would be to start on Vancomycin as unless otherwise proven all severe infections due to staphylococci community acquired are to be considered to be due to community acquired MRSA. We can de-escalate the antibiotics after the culture results come if needed.7
Dr. Dhanalakshmi It is day 17 of fever and the culture report shows MSSA sir. What about stopping Vancomycin and starting the kid on Cloxacillin monotherapy? What about continuing Aspirin and the follow up of the case sir?
We will start the kid on Cloxacillin 100 mg/kg/day for a total of 10 days and will continue to give Aspirin at 30 mg/kg/day for another 2 weeks. For MSSA, Cloxacillin is superior to Vancomycin. After 2 weeks we will repeat Echocardiography, CBC, ESR and CRP. If all the acute phase reactants have normalized and the child is also clinically well with Echo being normal, then we will decrease the Aspirin to 5 mg/kg/day and then follow up according to American Heart Association consensus guidelines.8
Dr. S. Balasubramanian Kawasaki disease with acute left staphylococcal suppurative cervical adenitis.
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pneumoniae to Kawasaki disease as a possible trigger. This is perhaps due to a super antigen or is mediated by some other mechanism. Accurate and timely testing for Mycoplasma infections is difficult and has its limitations. Despite this, Mycoplasma pneumoniae should be considered in the differential and workup for Kawasaki disease.12 The dilemma in this case was to start antibiotics or not. In this case, we started antibiotics after pus was obtained on incision. In retrospect we should have given antibiotics earlier. Also in this case, the “failure” to respond to the first dose of IVIg may be because the infection was not controlled and not due to a failure to respond to the 1st dose of IVIg per se. It is 2 weeks after draining pus and the infant has completely recovered. We plan to follow the infant’s status with an ECHO at 6 weeks.
Balasubramanian et al.
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PRACTICE PEARLS FROM THE EXPERT Dr Vijay Viswanathan (Pediatric Rheumatologist). 7. Kawasaki disease: a few clinically relevant points reviewed. 1. Tomisaku Kawasaki published the first Englishlanguage report of 50 patients with Kawasaki disease (KD) in 1974. Since that time, KD has become the leading cause of acquired heart disease among children in North America and Japan and cases in India seem to be on the rise mainly due to better awareness. 2. The causal agent of Kawasaki disease (KD) remains unknown after more than 40 years of intensive research. Superantigen toxins, role of IgA plasma cells in a genetically susceptible host have been postulated. 3. More recently analyses of the three major KD epidemics in Japan, major non-epidemic inter annual fluctuations of KD cases in Japan and San Diego, and the seasonal variation of KD in Japan, Hawaii, and San Diego, reveals a consistent pattern wherein KD cases are often linked to large-scale wind currents originating in central Asia and traversing the north Pacific. Results suggest that the environmental trigger for KD could be wind-borne.13 4. The classic diagnosis of Kawasaki disease has been based on the presence of 5 days of fever and 4 of the 5 principal clinical features. Typically, all of the clinical features are not present at a single point in time, and watchful waiting is sometimes necessary before a diagnosis can be made. In the presence of 4 principal criteria, the diagnosis of Kawasaki disease can be made on day 4 of illness. Kawasaki disease
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should be considered in the differential diagnosis of a young child with unexplained fever for 5 days that is associated with any of the principal clinical features of this disease. The term “incomplete” may be preferable to “atypical” because these patients lack sufficient clinical signs of the disease to fulfill the classic criteria; they do not demonstrate atypical clinical features. The phrase “atypical Kawasaki disease” should be reserved for patients who have a problem, such as renal impairment, that generally is not seen in Kawasaki disease. Incomplete Kawasaki disease should be considered in all children with unexplained fever for 5 days associated with 2 or 3 of the principal clinical features of Kawasaki disease Because young infants may present with fever and few, if any, principal clinical features (and a high chance of coronary changes), echocardiography should be considered in any infant aged 6 months with fever of 7 days’ duration, laboratory evidence of systemic inflammation, no other explanation for the febrile illness. The importance of BCG reactivation, gall bladder hydrops, sterile pyuria (documented pyuria plus a negative urine culture) cannot be overemphasized when dealing with incomplete cases. Also hypoalbuminemia, transaminitis along with thrombocytosis, neutrophilic leucocytosis and anemia add to the index of suspicion for KD. Occasionally thrombocytopenia can be seen and these are the cases who need to be followed up closely for complications. Coronary artery aneurysms or ectasia develop in 15%e25% of untreated children. The Japanese Ministry of Health criteria classify coronary arteries as abnormal if the internal lumen diameter is 3 mm in children 5 years old or 4 mm in children 5 years old; if the internal diameter of a segment measures 1.5 times that of an adjacent segment; or if the coronary lumen is clearly irregular. A Z score should always be sought from the cardiologist to document coronary dilatation. Treatment of KD with aspirin alone has never been subject to a randomized controlled trial, although aspirin versus aspirin plus IVIg has been studied. Meta-analysis comparing moderate anti-inflammatory doses of aspirin (30e50 mg/kg/day)14 with IVIg versus high dose aspirin (80e120 mg/kg/day) with IVIg found no significant difference in the incidence of CAA between the groups. Literature mentions a wide range as far as the anti-inflammatory dose of aspirin is concerned (30e100 mg/kg/d). Asian children are believed to experience more aspirin related
A one-year-old boy with cervical adenopathy and fever
toxicity hence 30e50 mg/kg/day is used in the Asian setting. To conclude, with current level of evidence, in a high risk clinical setting eg, GI bleeding secondary to vasculitis, hematemesis, a lower antiinflammatory dose (30e50 mg/kg can be used) with no difference in CAA risk. Aspirin may be reduced to anti platelet dose 48 h after fever defervesces. 10. Use of IVIg reduces the risk of cardiac involvement to 2%. IVIg resistance is defined as failure of fever to resolve after 36 h since finishing infusion. In these cases, a second IVIg is recommended. Though preferable to give within the first 10 days, in situations with ongoing inflammation, it should be given even after day 10 of illness. 11. Finally with current level of evidence it may be rational to use steroids in a resource poor setting like ours if a second IVIg fails, or access to biologicals (infliximab) not available. Studies have shown better defervescence of fever, normalization of labs with no significant bearing on coronary outcomes.
FUNDING
Case Files
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CONFLICTS OF INTEREST All authors have none to declare.
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REFERENCES 12. 1. Akagi T, Kato H, Inoue O, Sato N. A study on the optimal dose of aspirin therapy in Kawasaki disease e clinical evaluation and arachidonic acid metabolism. Kurume Med J. 1990;37:203e208. 2. Maconochie Ian K. Kawasaki disease Best Practice. Arch Dis Child Educ Pract Ed. 2004;89:ep3eep8. http://dx.doi.org/10. 1136/adc.2004.053728. 3. Leung DY, Giorno RC, Kazemi LV, Flynn PA, Busse JB. Evidence for superantigen involvement in cardiovascular
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injury due to Kawasaki syndrome. J Immunol. 1995;155: 5018e5021. Rowley AH, Shulman ST, Spike BT, Mask CA, Baker SC. Oligoclonal IgA response in the vascular wall in acute Kawasaki disease. J Immunol. 2001;166:1334e1343. Naoe S, Takahashi K, Masuda H, Tanaka N. Kawasaki disease. With particular emphasis on arterial lesions. Acta Pathol Jpn. 1991;41:785e797. Kawasaki T. Acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the fingers and toes in children [in Japanese]. Arerugi. 1967;16:178. Liu Catherine. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillinresistant Staphylococcus aureus infections in adults and children: executive summary. MRSA treatment guidelines. CID. 2011;52:285e292. 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. Circulation. 2004;110:2747e2771. Benseler SM, McCrindle BW, Silverman ED, Tyrrell PN, Wong J, Yeung RS. Infections and Kawasaki disease: implications for coronary artery outcome. Pediatrics. 2005;116: 760e766. Jan SL, Wu MC, Lin MC, Fu YC, Chan SC, Lin SJ. Pyuria is not always sterile in children with Kawasaki disease. Pediatr Int. 2010;52:113e117. Shike H, Shimizu C, Kanegaye JT, et al. Adenovirus, adenoassociated virus and Kawasaki disease. Pediatr Infect Dis J. 2005;24:1011e1014. Ebrahim M, Gabay M, Rivas-Chacon RF. Evidence of acute mycoplasma infection in a patient with incomplete and atypical Kawasaki disease: a case report. Case Rep Med; 2011: 606920. Rodó X, Ballester J, Cayan D, et al. Association of Kawasaki disease with tropospheric wind patterns. Scientific Reports. 2011;1(152). Brogan PA, Bose A, Burgner D, et al. Kawasaki disease: an evidence based approach to diagnosis, treatment, and proposals for future research. Arch Dis Child. 2002;86:286e290.