An 11-month-old Girl with High Fever

Abstract

<div class="ftContainer"> <style> ol{ list-style-type:none; } </style> <div class="ftAuthorNotes"> <p>Tugba Erener Ercan, MD; Gokmen Ercan, MD; and Muhsin Arpaozu, MD, are with Maltepe University Medical Faculty, Department of Pediatrics, Istanbul, Turkey. </p> <p>Dr. Tugba Erener Ercan; Dr. Gokmen Ercan; and Dr. Arpaozu have disclosed no relevant financial relationships.</p> <p>Address correspondence to: Tugba Erener Ercan, MD, Maltepe Universitesi Hastanesi, Ataturk Cad. Cam Sok. No. 3, 034843, Maltepe, Istanbul, Turkey; 90 216 370 97 19; e-mail address: tugbaerener@yahoo.com. </p> </div> <div class="ftArticle"> <p>An 11-month-old girl was admitted to our outpatient pediatrics clinic with the complaint of high fever, which appeared the night before admission. She has been followed up in our pediatrics clinic regularly for her well-child visits since she was 3 months old. Her medical history was insignificant, and she was fully immunized for age including Bacillus Calmette-Guérin (BCG) vaccination. She was well looking despite her high fever (39 ° C). On physical examination, no significant findings except for a mild hyperemia of the oropharynx were found. Complete blood count revealed a hemoglobin level of 12.2 g/dL and thrombocyte level of 468,000/mm <sup>3</sup>. ESR was 75 mm/h, and CRP was 3.15 mg/dL (normal: < 0.5 mg/dL). The urinalysis showed pyuria and after a urine culture was taken, she was given parenteral antibiotics (ceftriaxone 75 mg/kg) for the diagnosis of a urinary tract infection. </p> <p> <b>For diagnosis, see page 307</b> </p> <p>After the second dose of her antibiotic, she presented to our out-patient clinic for a follow-up visit. Her daily fever continued despite the antibiotic treatment. Her mother complained that there was redness on her arm around the localization of her BCG scar. Her physical examination revealed an erythema and induration of 3 x 3 cm in diameter involving the BCG scar (see Figure <a href="#x00904481-20090508-02-fig1">1</a>, page 305, and Figure <a href="#x00904481-20090508-02-fig2">2</a>). At this visit, she was irritable, and she had more marked erythema of the oropharynx with mildly erythematous lips and a mild conjunctival injection. Meanwhile, her urine culture and blood culture remained sterile. </p> <a name="x00904481-20090508-02-fig1"></a> <table class="ftFigure"> <tr> <td class="ftGraphicThumbnail"> <a target="_blank" href="/images/content/PED/2009/10.3928_00904481-20090508-02-fig1.jpg"> <img class="ftThumbnail" alt="Induration of 3 × 3 cm in Diameter Involving the BCG Scar." src="/images/content/PED/2009/10.3928_00904481-20090508-02-fig1.jpg"></img> </a> </td> <td class="ftFigureCaption"> <p class="ftFloatLeft">Figure 1. Induration of 3 × 3 cm in Diameter Involving the BCG Scar.</p> </td> </tr> </table> <a name="x00904481-20090508-02-fig2"></a> <table class="ftFigure"> <tr> <td class="ftGraphicThumbnail"> <a target="_blank" href="/images/content/PED/2009/10.3928_00904481-20090508-02-fig2.jpg"> <img class="ftThumbnail" alt="Erythema of 3 × 3 cm in Diameter Involving the BCG Scar." src="/images/content/PED/2009/10.3928_00904481-20090508-02-fig2.jpg"></img> </a> </td> <td class="ftFigureCaption"> <p class="ftFloatLeft">Figure 2. Erythema of 3 × 3 cm in Diameter Involving the BCG Scar.</p> </td> </tr> </table> <p>The inflammation of the BCG scar and the continuing daily fever with more marked erythema of the oropharynx led us to the presumptive diagnosis of incomplete Kawasaki disease on the third day of her fever. Her complete blood count showed a thrombocyte level of 519,000/mm <sup>3</sup>. ESR was 95 mm/h, and CRP was 3.09 mg/dL. Blood biochemistry was all normal except for hypoalbuminemia (2.9 g/dL). Cerebrospinal fluid examination was normal. Viral serology including Epstein-Barr virus and adenovirus was negative. Immunoglobulin levels were all normal. Abdominal ultrasonography revealed no pathology. Echocardiography showed no abnormalities involving coronary arteries. </p> <p>On the fourth day of her fever, her erythematous lips became fissured, and conjunctival injection became more noticeable. A maculopapular rash appeared over the trunk and extremities. There were no changes on extremities and no lymphadenopathy was detected. </p> <div class="ftSection"> <h3>Diagnosis</h3> <p> <b>Kawasaki Disease</b> </p> <p>Despite antibiotic treatment, her fever continued as did other findings (conjunctivitis, erythematous lips, and a maculopapular rash) suggestive of Kawasaki disease appeared, in addition to the inflammation of the BCG scar. Therefore, a diagnosis of incomplete Kawasaki disease was made. She was started on IV immune globulin therapy (IVIG, 2 gr/kg over 12 hours) and aspirin (80 mg/kg) on the sixth day of fever. The fever subsided dramatically after IVIG therapy, and erythema around the BCG scar disappeared. Subsequent complete blood count in the second week of illness demonstrated an increase in the thrombocyte level (808,000/mm <sup>3</sup>). Her repeat echocardiography 3 weeks after disease onset also revealed no abnormalities. Convalescent phase was unremarkable, and aspirin therapy was continued for 8 weeks. </p> </div> <div class="ftSection"> <h3>Discussion</h3> <p>Kawasaki disease is a multiorgan vasculitis that occurs predominantly in infants and young children. <sup> <a href="#x00904481-20090508-02-bibr1">1</a> </sup> Coronary artery aneurysms or ectasia develop in untreated patients. This is a case of an 11-month-old, fully immunized, girl whose BCG scar reactivation led us to an earlier diagnosis of incomplete Kawasaki disease. This rare but specific sign of Kawasaki disease can be used as a tool for an early diagnosis of Kawasaki/incomplete Kawasaki disease especially in countries where BCG vaccination is still a part of the immunization schedule, as in our country of Turkey. </p> <p>Kawasaki disease was first described in Japan by Tomisaku Kawasaki in 1967. The etiology of Kawasaki disease remains unknown. Kawasaki disease is characterized by fever lasting 5 days or more (without other explanation), bilateral nonexudative conjunctivitis, erythema of the lips and oral mucosa, changes in the extremities, rash, and cervical adenopathy. Fever with at least four of the five principal clinical findings is needed for its diagnosis. <sup> <a href="#x00904481-20090508-02-bibr2">2</a> </sup> Coronary artery aneurysms or ectasia develop in 15% to 25% of untreated children. <sup> <a href="#x00904481-20090508-02-bibr1">1,3</a> </sup> Early diagnosis and prompt treatment of the acute syndrome is critical for preventing life threatening complications. However, diagnosis of the syndrome is based on signs and symptoms that also occur in other pediatric illnesses, which can result in diagnostic dilemmas, especially in atypical cases. In patients with fever and in fewer than four of the principal diagnostic features, detection of coronary artery abnormalities by two-dimensional echocardiography should lead to the diagnosis of atypical Kawasaki disease. <sup> <a href="#x00904481-20090508-02-bibr4">4-7</a> </sup> Although it is not included in the diagnostic criteria of Kawasaki disease, reactivation of a BCG scar that is characterized by erythema and induration of a previous BCG inoculation site is an important and specific sign of Kawasaki disease. <sup> <a href="#x00904481-20090508-02-bibr8">8-12</a> </sup> </p> <p>Kawasaki disease neither has a known etiology nor has a specific diagnostic test to confirm it. The diagnosis of Kawasaki disease has been based on the presence of fever for 5 or more days without other explanation and four of the five principal clinical features. <sup> <a href="#x00904481-20090508-02-bibr2">2</a> </sup> In 1987, Sonobe and Kawasaki <sup> <a href="#x00904481-20090508-02-bibr13">13</a> </sup> stated that the presence of fewer than four of the principal clinical features accompanying fever and presence of coronary artery aneurysms allows the diagnosis of atypical Kawasaki disease. Atypical or incomplete cases of Kawasaki syndrome are being recognized with increasing frequency. <sup> <a href="#x00904481-20090508-02-bibr4">4</a> </sup> Up to 10% to 45% of children are postulated to have an atypical or incomplete course. <sup> <a href="#x00904481-20090508-02-bibr14">14</a> </sup> Early diagnosis of Kawasaki disease is extremely important since coronary artery aneurysms occur as a sequela of the vasculitis in 15% to 25% of untreated children. <sup> <a href="#x00904481-20090508-02-bibr1">1,3,7</a> </sup> In the literature, ages of the patients with atypical Kawasaki syndrome were reported to be between 2 months and 15 years. <sup> <a href="#x00904481-20090508-02-bibr15">15</a> </sup> Atypical Kawasaki syndrome is mainly seen in children younger than 6 months, and cardiovascular complications are most common in young infants. </p> <p>The American Heart Association recommends that echocardiography should be considered in any infant younger than 6 months with fever of 7 days or more in duration without any other explanation and laboratory evidence of systemic inflammation. Incomplete Kawasaki disease should be considered in any child with unexplained fever for 5 days with two or three of the principal clinical features of classic Kawasaki disease. <sup> <a href="#x00904481-20090508-02-bibr7">7</a> </sup> </p> <p>Therefore, any finding that could lead to early diagnosis is worth taking into consideration. Erythema and induration of a previous BCG inoculation site is a specific and early manifestation of KD. <sup> <a href="#x00904481-20090508-02-bibr10">10-12,16</a> </sup> The local inflammatory reactivation of a BCG vaccination site was first highlighted in the Japanese literature as a specific and an early sign of Kawasaki disease. <sup> <a href="#x00904481-20090508-02-bibr17">17</a> </sup> </p> <p>This inflammatory reactivation was hypothetically ascribed to the cross-reactivity between mycobacterial Heat Shock Protein (HSP) 65 and Human Homologue HSP63, which is a mitochondrial protein. <sup> <a href="#x00904481-20090508-02-bibr11">11,12,18</a> </sup> Studies have shown that T-cells obtained from the peripheral blood of KD patients recognize an epitope from HSP 65 and cross-reacted with the corresponding peptide sequence of human HSP 63. <sup> <a href="#x00904481-20090508-02-bibr12">12,19</a> </sup> </p> <p>There are few case reports emphasizing the usefulness of the inflammatory reactivation of BCG vaccination site in the diagnosis of Kawasaki disease, especially incomplete Kawasaki disease. </p> <p>Our patient had a persistent fever despite antibiotic treatment. During the first few days of her fever, she had no typical physical findings suggestive of Kawasaki disease except for an erythema and induration of her BCG vaccination site, which led us to the suspicion of Kawasaki disease on the third day of illness. During follow up, she developed three of the five specific clinical findings suggestive of incomplete Kawasaki disease in addition to her persistent fever, increased acute phase reactants, and sterile pyuria, which is seen in 33 % of Kawasaki disease patients. <sup> <a href="#x00904481-20090508-02-bibr7">7</a> </sup> With early diagnosis and treatment, prompt resolution of her symptoms occurred without any sequela involving coronary arteries. </p> </div> <div class="ftSection"> <h3>Conclusion</h3> <p>Because Kawasaki/incomplete Kawasaki disease is a diagnostic dilemma, any sign that could help early diagnosis is useful. Inflammatory reactivation of a BCG vaccination site is an early and specific sign of Kawasaki disease. BCG vaccination is part of the national immunization schedule in Turkey. With this case report, we tried to emphasize the usefulness of BCG site reactivation in establishing a diagnosis of Kawasaki/incomplete Kawasaki syndrome so that clinicians should be aware of this clinical manifestation especially in countries where BCG vaccination is still a part of the immunization schedule. </p> </div> <div class="ftRefList"> <h3>References</h3> <ol> <a name="x00904481-20090508-02-bibr1"></a> <li> Dajani AS, Taubert KA, Gerber MA, et al. Diagnosis and therapy of Kawasaki disease in children. <i>Circulation</i>. 1993;87(5):1776-1780. </li> <a name="x00904481-20090508-02-bibr2"></a> <li> Rowley AH, Shulman ST. Kawasaki Disease. In: <i>Nelson’s Text Book of Pediatrics</i>. 17th ed. Behrman RE, Kliegman RM, Jenson HB, eds. Elsevier; 2004:823-826. </li> <a name="x00904481-20090508-02-bibr3"></a> <li> Kato H, Sugimura T, Akagi T, et al. Long-term consequences of Kawasaki disease. A 10- to 21-year follow-up study of 594 patients. <i>Circulation</i>. 1996;94(6):1379-1385. </li> <a name="x00904481-20090508-02-bibr4"></a> <li> Witt MT, Minich LL, Bohnsack JF, Young PC. Kawasaki disease: patients are being diagnosed who do not meet American Heart Association criteria. <i>Pediatrics</i>. 1999;104(1):10. doi:10.1542/peds.104.1.e10 <a target="_blank" href="http://dx.doi.org/10.1542/peds.104.1.e10"> [CrossRef]</a> </li> <a name="x00904481-20090508-02-bibr5"></a> <li> Pfafferott C, Wirtzfeld A, Permanetter B. Atypical Kawasaki syndrome: how many symptoms have to be present? <i>Heart</i>. 1997;78(6):619-621. </li> <a name="x00904481-20090508-02-bibr6"></a> <li> Boven K, De Graeff-Meeder ER, Spliet W, Kuis W. Atypical Kawasaki disease: an often missed diagnosis. <i>Eur J Pediatr</i>. 1992;151(8):577-580. doi:10.1007/BF01957725 <a target="_blank" href="http://dx.doi.org/10.1007/BF01957725"> [CrossRef]</a> </li> <a name="x00904481-20090508-02-bibr7"></a> <li> Newburger JW, Takahashi M, Gerber MA, et al. Committee on Rheumatic Fever, Endocarditis and Kawasaki DiseaseCouncil on Cardiovascular Disease in the YoungAmerican Heart Association; American Academy of Pediatrics. Diagnosis, treatment, and long-term management of Kawasaki disease. <i>Circulation</i>. 2004;110(17):2747-2771. doi:10.1161/01.CIR.0000145143.19711.78 <a target="_blank" href="http://dx.doi.org/10.1161/01.CIR.0000145143.19711.78"> [CrossRef]</a> </li> <a name="x00904481-20090508-02-bibr8"></a> <li> Brogan PA, Bose A, Burgner O, et al. Kawasaki disease: an evidence based approach to diagnosis, treatment and proposals for future research. <i>Arch Dis Child</i>. 2002;86(4):288-290. doi:10.1136/adc.86.4.286 <a target="_blank" href="http://dx.doi.org/10.1136/adc.86.4.286"> [CrossRef]</a> </li> <a name="x00904481-20090508-02-bibr9"></a> <li> Hsu YH, Wang YH, Hsu WY, Lee YP. Kawasaki disease characterized by erythema and induration at the Bacillus Calmette-Guérin and purified protein derivative inoculation sites. <i>Pediatr Infect Dis J</i>. 1987;6(6):576-578. </li> <a name="x00904481-20090508-02-bibr10"></a> <li> Plantin P, Blayo M, Dupre D, et al. BCG reactivation: a rare but specific sign of Kawasaki disease. <i>Presse Med</i>. 1998;27(15):716. </li> <a name="x00904481-20090508-02-bibr11"></a> <li> Sinha R, Balakumar T. BCG reactivation: a useful diagnostic tool even for incomplete Kawasaki disease. <i>Arch Dis Child</i>. 2005;90(9):891. doi:10.1136/adc.2004.071332 <a target="_blank" href="http://dx.doi.org/10.1136/adc.2004.071332"> [CrossRef]</a> </li> <a name="x00904481-20090508-02-bibr12"></a> <li> Antony D, Jessy PL. Involvement of BCG scar in Kawasaki disease. <i>Indian Pediatr</i>. 2005;42(1):83-84. </li> <a name="x00904481-20090508-02-bibr13"></a> <li> Sonobe T, Kawasaki T. Atypical Kawasaki disease. <i>Prog Clin Biol Res</i>. 1987;250:367-378. </li> <a name="x00904481-20090508-02-bibr14"></a> <li> Kusinska B, Wróblewska-Kaluzewska M. What do we know about Kawasaki disease? <i>Med Sci Monit</i>. 2000;6(6):1227-1231. </li> <a name="x00904481-20090508-02-bibr15"></a> <li> Levi M, Koren G. Atypical Kawasaki disease: analysis of clinical presentation and diagnostic clues. <i>Pediatr Infect Dis J</i>. 1990;9(2):122-126. </li> <a name="x00904481-20090508-02-bibr16"></a> <li> Kuniyuki S, Asada M. An ulcerated lesion at the BCG vaccination site during the course of Kawasaki disease. <i>J Am Acad Dermatol</i>. 1997;37(2 Pt 2):303-304. doi:10.1016/S0190-9622(97)70011-2 <a target="_blank" href="http://dx.doi.org/10.1016/S0190-9622(97)70011-2"> [CrossRef]</a> </li> <a name="x00904481-20090508-02-bibr17"></a> <li> Takayama J, Yanase Y, Kawasaki T. Study of the changes of the site of the BCG inoculation in MCLS. <i>Jpn J Pediatr</i>. 1982;86:567-572. </li> <a name="x00904481-20090508-02-bibr18"></a> <li> Yokota S, Tsubaki K, Kuriyama T, et al. Presence in Kawasaki disease of antibodies to mycobacterial heatshock protein HSP65 and autoantibodies to epitopes of human HSP63 cognate antigen. <i>Clin Immunol Immunopathol</i>. 1993;67(2):163-170. doi:10.1006/clin.1993.1060 <a target="_blank" href="http://dx.doi.org/10.1006/clin.1993.1060"> [CrossRef]</a> </li> <a name="x00904481-20090508-02-bibr19"></a> <li> Sireci G, Diell F, Salerno A. T cells recognize an Immunodominant epitope of heat shock protein 65 in Kawasaki disease. <i>Mol Med</i>. 2000;6(7):581-590. </li> </ol> </div> <span class="ftTitle">Editor’s Note:</span> <p>Each month, this department features a discussion of an unusual diagnosis in genetics, radiology, or dermatology. A description and images are presented, with the diagnosis and an explanation of how the diagnosis was determined following. As always, your comments are welcome. </p> <div class="ftSidebarText"></div> </div> </div>

Erythema at BCG Inoculation Site in Kawasaki Disease Patients

“…They showed that this sign appears in the early stage of the disease, between 1 and 4 days after the onset of the illness by fever (3). Similar finding was reported by Hsu et al in 1986 and others (1,8,16). …”

“…Also, thrombocytopenia is unusual in KD, but it is considered as a risk factor for the development of aneurism(33). In this review, among supplementary laboratory findings to diagnosing KD in patients with BCGitis we found elevated CRP more than 3 mg (8,14,16,26), increased ESR more than 40 mm/h (8,13,16,26), elevated alanine aminotransferase (1,14), Leukocytosis (13,14), normochromic, normocytic anaemia (13,16,26), sterile pyuria more than 10 white blood cell/mm 3 (1,8,22), thrombocytosis and thrombocytopenia (1,8,16,21-24,26). …”

“…However, IVIG should also be given to patients who present after the 10 th day of illness (32). In this review, 20 patients were reported to receive IVIG therapy (8,16,19,23). In 2009, Ercan et al from Turkey reported an 11-month-old girl with high fever associated with other manifestations such as conjunctivitis, erythematous lips, and a maculopapular rash.…”

“…Besides, BCG vaccination was as a part of the national immunization schedule in Turkey. So that, they tried to emphasize the usefulness of BCG site reactivation in establishing a diagnosis of Kawasaki/incomplete Kawasaki syndrome that clinicians should be aware of this clinical manifestation especially in countries where BCG vaccination is still a part of the immunization schedule (8). Similarly, Sinha et al, in 2007 presented three cases of IKD to show the usefulness of BCG reactivation in formulating a diagnosis of Incomplete Kawasaki.…”

“…Early diagnosis of KD is very important, because coronary artery aneurysms occur as a result of vasculitis in 15% to 25% of untreated children (8). Coronary artery lesions (CAL) or coronary artery abnormalities (CAA), myocardial infarction, coronary artery fistula, coronary artery dilatation (CAD), and coronary artery aneurysm (CAA) are the most serious side effects of KD (2).…”