The Pediatric Infectious Disease Journal • Volume 33, Number 6, June 2014
Many biomarkers for KD have been proposed, particularly inflammatory response markers, but no individual biomarker is likely to be diagnostic.9–14 We tested periostin as a possible serum biomarker, because markers of cardiac/vascular injury could be very helpful in differentiating children with KD from children with benign febrile illnesses that do not manifest cardiac pathology. The N-terminal moiety of brain natriuretic peptide (NTproBNP), a cardiac hormone secreted by ventricular cardiomyocytes in response to stress, may also be useful in this regard.9–11,14 It is interesting that in our study, serum periostin levels were increased in some KD patients with echocardiographically normal coronary arteries. It is possible that elevated serum periostin levels in acute KD could result from myocarditis, which is common in the acute phase.15 Our study has several limitations. The target tissue of KD, the coronary artery, is inaccessible to the researcher in living patients, and fortunately, fatalities are unusual. These tissues are available only as autopsy and explanted heart specimens and are thus rare, which accounts for the relatively small sample size of coronary artery tissues in this study. Our labarotory houses 1 of the largest collections of such tissues in North America. We performed immunohistochemistry on KD coronary artery tissues using 2 different commercially available antihuman periostin antibodies, but were unable to determine whether periostin protein was present diffusely in the sections or whether these antibodies resulted in nonspecific staining. We plan to perform ELISA studies on serial acute and convalescent KD sera to evaluate periostin expression levels over time in a future study. In summary, periostin is upregulated in KD coronary tissues, and markedly increased periostin levels are detected in the sera of a subset of KD patients. We propose that a KD biomarker panel be developed and evaluated in a multicenter trial and periostin be included in this panel. The development of diagnostic tools to facilitate rapid therapeutic intervention is essential for this potentially devastating childhood disease.
Periostin in Kawasaki Disease
8. Samsonov MY, Tilz GP, Pisklakov VP, et al. Serum-soluble receptors for tumor necrosis factor-alpha and interleukin-2, and neopterin in acute rheumatic fever. Clin Immunol Immunopathol. 1995;74:31–34. 9. Dahdah N, Siles A, Fournier A, et al. Natriuretic peptide as an adjunctive diagnostic test in the acute phase of Kawasaki disease. Pediatr Cardiol. 2009;30:810–817. 10. Kaneko K, Yoshimura K, Ohashi A, et al. Prediction of the risk of coronary arterial lesions in Kawasaki disease by brain natriuretic peptide. Pediatr Cardiol. 2011;32:1106–1109. 11. Sato YZ, Molkara DP, Daniels LB, et al. Cardiovascular biomarkers in acute Kawasaki disease. Int J Cardiol. 2013;164:58–63. 12. Ling XB, Lau K, Kanegaye JT, et al. A diagnostic algorithm combining clinical and molecular data distinguishes Kawasaki disease from other febrile illnesses. BMC Med. 2011;9:130. 13. Kentsis A, Shulman A, Ahmed S, et al. Urine proteomics for discovery of improved diagnostic markers of Kawasaki disease. EMBO Mol Med. 2013;5:210–220. 14. McNeal-Davidson A, Fournier A, Spigelblatt L, et al. Value of amino-terminal pro B-natriuretic peptide in diagnosing Kawasaki disease. Pediatr Int. 2012;54:627–633. 15. Harada M, Yokouchi Y, Oharaseki T, et al. Histopathological characteristics of myocarditis in acute-phase Kawasaki disease. Histopathology. 2012;61:1156–1167.
BORDETELLA HOLMESII ENDOCARDITIS CASE REPORT AND REVIEW OF LITERATURE
Amy P. Couturier, MD* and Karen Dahl, MD† Abstract: The second case of Bordetella holmesii endocarditis in a pediatric patient is presented. This patient had a prosthetic mitral valve and asplenia. He was successfully treated with 6 weeks of intravenous meropenem. We review all 9 other reported cases of endocarditis and summarize treatment and outcome. Five were immunocompromised and 6 had predisposing cardiac conditions. Key Words: Bordetella holmesii, endocarditis, asplenia, immunocompromise
ACKNOWLEDGMENTS We thank Robin Biggs, Deidre Anderson and Leslie Martin for assistance in identifying and dissecting control coronary artery samples and Moheet Merchant for organization of serum banking. REFERENCES 1. Newburger JW, Takahashi M, Gerber MA, et al.; Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. 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. Pediatrics. 2004;114:1708–1733. 2. Orenstein JM, Shulman ST, Fox LM, et al. Three linked vasculopathic processes characterize Kawasaki disease: a light and transmission electron microscopic study. PLoS One. 2012;7:e38998. 3. Reindel R, Baker SC, Kim KY, et al. Integrins α4 and αM, collagen1A1, and matrix metalloproteinase 7 are upregulated in acute Kawasaki disease vasculopathy. Pediatr Res. 2013;73:332–336. 4. Frangogiannis NG. Matricellular proteins in cardiac adaptation and disease. Physiol Rev. 2012;92:635–688. 5. Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 2008;3:1101–1108. 6. Matsubara T, Furukawa S, Yabuta K. Serum levels of tumor necrosis factor, interleukin 2 receptor, and interferon-gamma in Kawasaki disease involved coronary-artery lesions. Clin Immunol Immunopathol. 1990;56:29–36. 7. Kurane I, Innis BL, Nimmannitya S, et al. Activation of T lymphocytes in dengue virus infections. High levels of soluble interleukin 2 receptor, soluble CD4, soluble CD8, interleukin 2, and interferon-gamma in sera of children with dengue. J Clin Invest. 1991;88:1473–1480.
© 2014 Lippincott Williams & Wilkins
Accepted for publication December 4, 2013. From the *Michigan State University College of Human Medicine; and †Pediatric Infectious Disease Spectrum Health Medical Group, Helen DeVos Children’s Hospital, Michigan State University College of Human Medicine, Grand Rapids, MI. The authors have no funding or conflict of interest to disclose. Address for correspondence: Karen Dahl, MD, Division Chief, Pediatric Infectious Disease, Helen DeVos Children’s Hospital, 100 Michigan St NE Mail Code 177, Grand Rapids, MI 49503. E-mail: [email protected]. Copyright © 2014 by Lippincott Williams & Wilkins DOI: 10.1097/INF.0000000000000234
B
ordetella holmesii is a rare cause of endocarditis reported most often in immunocompromised or asplenic patients. We present the second pediatric case reported in the literature. There have been 9 other cases of B. holmesii endocarditis reported in the literature and 6 had underlying cardiac conditions.
CASE REPORT This 9-year-old male presented with diarrhea, fatigue and low grade fever. His past medical history was significant for anatomical asplenia and congenital heart disease (dextrocardia with a complete atrioventricular canal defect, double outlet right ventricle and pulmonary stenosis), status post closure of atrial septal defect and ventricular septal defect, resection of the infundibular septum, placement of an intraventricular baffle from the left ventricle to www.pidj.com | 661
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Couturier and Dahl
TABLE 1. Summary of Documented Bordetella holmesii Endocarditis Cases Authors Tang et al7
Age/Sex 25 years/male
Immunocompromised/ Medical History No (remote history of Hodgkin’s disease)
Echocardiogram Findings
Cardiac History Bicuspid aortic valve
Aortic valve vegetation
Shepard et al5 35 years/male
Unknown
Aortic valvular abscess
Shepard et al5 Clare et al4
Unknown None
Unknown Aortic valve vegetation
Jonckheere et al2
Yes (asplenia, h istory of Hodgkin’s disease) Unknown Unknown 33 years/female Yes (asplenia) 36 years/male
No (chronic alcohol and tobacco use)
Bassetti et al8 48 years/male
Russell et al3
Yes (systemic lupus erythematous, azathropine and prednisone) 14 years/female No
Not mentioned
Unknown Cefotaxime 2 g TID* for 4 weeks Meropenem
Unknown Aortic valve replacement
Aortic valve replacement
Yes
Complete recovery Survived Survived Complete recovery
Aortic valve vegetation
Meropenem 1 g TID
None
Mitral valve prolapse and moderate mitral regurgitation Pulmonary, aortic, and mitral valve vegetations No vegetations initially. At second relapse, aortic valve vegetation No vegetations
Cefotaxime for 6 weeks
None
Pulmonary fibrosis
Ceftriaxone 1 g BID† for 4 weeks
None
Complete recovery
Aortic valve replacement
Bush et al6
80 years/male
Bioprosthetic aortic valve, permanent cardiac pacemaker
Yes (asplenia)
Ceftriaxone 2 g daily for 4 weeks Unknown
Outcome
Aortic valve vegetation and destruction of another leaflet
52 years/female Yes (asplenia, history of Hodgkin’s disease)
Couturier and 9 years/male Dahl
Cardiac Surgical Intervention
Streptococcus bovis endocarditis on post-rheumatic aortic and mitral valves; aortic homograft and mitral mechanical valve Bicuspid aortic valve
Soloaga et al9
No
Antibiotic Therapy
Complex congenital heart disease with mechanical mitral valve
Multiple courses‡
Meropenem 20 mg/ kg/dose TID for 6 weeks
Aortic Complete homograft recovery replaced with mechanical composite valve
Aortic valve replacement after second relapse None
Complete recovery
Right embolic stroke, complete recovery Complete recovery
* TID = every 8 hours. †BID = every 12 hours. ‡Etrapenem, 8 weeks; ceftriaxone, 25 days followed by suppressive oral therapy; ertapenem, 6 weeks.
the aorta, placement of a conduit from the right ventricle to the pulmonary artery and baffling of the left sided inferior vena cava to the right atrium. His most recent cardiac surgery was 6 years ago for prosthetic mitral valve replacement with cardiac baffles. He required multiple procedures for dental caries. He was prescribed warfarin because of his prosthetic valve. Because of his asplenic status, he was prescribed amoxicillin prophylaxis 500 mg daily but he is known to only be partially compliant. All other history was unrelated to his presenting illness. For 3 weeks before admission, the patient had symptoms of diarrhea and required hydration therapy in the emergency department 1 time. Then, he developed a fever of 38.3°C, had decreased appetite, fatigue, sweats and chills and was admitted for evaluation. A blood culture was obtained and therapy with vancomycin and ceftriaxone was initiated. The blood culture remained negative and the patient clinically improved over the course of 4 days. A transthoracic echocardiogram was obtained and did not reveal vegetations or changes from baseline. A transesophageal echocardiogram was considered but not done, as the family did not want to pursue surgical intervention even if there were definitive findings of endocarditis. Culture-negative bacterial endocarditis was suspected due to his underlying
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cardiac disease, history of documented fever and partial adherence with amoxicillin prophylaxis. The family refused further treatment for endocarditis and the patient was discharged with close follow up. The day after discharge, and after 5 days of incubation, the microbiology laboratory reported an unidentified Gram-negative bacterium from the initial blood culture on previous admission. Two subsequent cultures obtained during the hospital admission were sterile. The patient was contacted at home and another blood culture was obtained outpatient but the family refused admission. After 4 days of incubation, this also grew Gram-negative bacilli and the patient was then admitted for treatment of Gram-negative bacteremia and suspected endocarditis. On physical examination, he was well-appearing. His temperature was 38.1°C, respiratory rate of 20 breaths/min, heart rate of 97 beats/min and blood pressure of 107/72 mm Hg. The cardiovascular exam revealed a regular rhythm with a baseline 3/6 systolic ejection murmur loudest at the upper right sternal border and mechanical click. There was no splinter or conjunctival hemorrhages. The remainder of his exam was unremarkable. Laboratory studies revealed a white blood cell count of 16.08 × 103 cells/uL, hemoglobin of 10.1 g/dL and platelets of 378 × 103 cells/uL. A © 2014 Lippincott Williams & Wilkins
The Pediatric Infectious Disease Journal • Volume 33, Number 6, June 2014
complete metabolic panel was significant for calcium of 7.9 mg/ dL, total protein of 5.1 g/dL and an albumin of 2.1 g/dL. A C-reactive protein was 69.7 mg/L (normal < 10 mg/L). Another blood culture was obtained on admission, which was positive after 3 days of incubation. The Pediatric Infectious Disease consultant suspected endocarditis, most likely caused by a HACEK organism (an acronym for fastidious Gram-negative bacilli that are recognized endocarditis pathogens).1 The diagnosis of possible infective endocarditis was based on the modified Duke’s criteria: growth of a potential pathogen on 2 separate blood cultures (1 major); predisposing heart condition and fever (2 minor). He was treated with ceftriaxone, 2 g daily, based on The American Heart Association infective endocarditis guideline.1 The Gram-negative bacterium from his blood culture was sent to the Michigan Department of Community Health and was identified as B. holmesii. Based on the isolate’s minimum inhibitory concentration and a case report of a patient with B. holmesii endocarditis with prosthetic valve who was successfully treated with meropenem,2 antibiotics were changed to meropenem 20 mg/ kg every 8 hours for 6 weeks. The MICs for the patient’s isolate were: ceftriaxone ≥32 ug/mL, meropenem = 0.064 ug/mL and azithromycin = 0.125 ug/mL. A follow-up echocardiogram after completion of 6 weeks of meropenem was unchanged. After meropenem therapy was completed, suppressive therapy with azithromycin was recommended because of the presence of the prosthetic valve and concern for relapse. The patient has been nonadherent with this regimen but after 6 months has remained well.
DISCUSSION A comprehensive PubMed English language literature search of all reported B. holmesii human endocarditis cases was conducted. The terms Bordetella AND holmesii AND endocarditis were used. Additional references from identified articles were reviewed. There are 9 other cases of B. holmesii endocarditis reported in the literature and all are included in our review. We reviewed 1 other pediatric case and 8 adult cases for cardiac history, immunocompromising conditions, echocardiogram findings, treatment and outcome (Table 1). The first pediatric case was presented by Russell et al3. This previously healthy 14-year-old female presented with echocardiogram findings of mitral valve prolapse and moderate mitral regurgitation but no vegetations or pericardial fluid. B. holmesii was isolated repeatedly in blood cultures and she was treated with cefotaxime for 6 weeks for possible endocarditis. Our case report is the second pediatric case of endocarditis which was suspected and treated without evidence of vegetations on echocardiogram. Half of all reported patients with B. holmesii endocarditis were immunocompromised, most commonly due to asplenia. The majority (6 of 10) had predisposing cardiac conditions. It is important to note, however, that 2 patients were previously healthy, without immunocompromise or underlying cardiac disease. At least 5 patients required surgical intervention for valvular replacement and 1 patient with a prosthetic valve relapsed twice after initial presentation. All patients recovered with either medical or medical and surgical treatment and no deaths were reported. B. holmesii was first discovered in 1983 and named in 1995 in honor of Barry Holmes for his contributions in bacteriology. Since then, only case reports have been published. Disease severity ranges from bacteremia to endocarditis requiring surgery and extended hospital stay. Pneumonia, bacteremia with septic shock, © 2014 Lippincott Williams & Wilkins
B. holmesii Endocarditis
cellulitis and suppurative arthritis have also been reported.4 It is evident from the literature that B. holmesii has a predilection for asplenic patients and/or immunocompromised hosts of any age. Shepard et al5 published Centers for Disease Control data for 26 cases of bacteremia with B. holmesii, of which 22 were asplenic. The association not only may be due to immunodeficiency resulting from asplenia that increases the risk for infection but also may be explained by reporting bias of clinicians who are more likely to pursue identification of an isolate in an immunocompromised host.5 Classically, asplenic patients have a predilection for encaspulsated organisms; however, B. holmesii is not known to possess a polysaccharide capsule.6 Defining the microbiologic characteristics has been challenging due to the paucity of isolates and the slow growing nature of the bacterium. B. holmesii is a small, nonmotile, nonhemolytic, catalase-negative, aerobic Gram-negative bacilli that grows best on blood and chocolate agar after at least 48 hours of incubation.6 Its production of a brown soluble pigment when grown on MacConkey agar is specific for B. holmesii.6 Interestingly, Bordetellae oxidize amino acids but generally do not metabolize carbohydrates.6. In some cases, B. holmesii has been confused with Acinetobacter species due to similar microbiologic characteristics; however, Acinetobacter does not produce the brown pigment on MacConkey agar and is catalase positive.6 To best identify the organism, a 16S rRNA gene sequence can determine speciesspecific regions of 20–30 bases and homology sequencing can be compared with known isolates.7 Strain-specific minimum inhibitory concentration should be used for treatment because practice guidelines do not exist for this organism. Endocarditis has been successfully treated with ceftriaxone 2 g daily or meropenem 1–2 g every 8 hours for 4–6 weeks. It should be noted that some isolates are resistant to cephalosporins. Resistance patterns raise a concern for extended spectrum betalactamase production that has not been well-documented but is important to consider in treatment decisions.8 There is a considerable amount of information that is still unknown about B. holmesii especially regarding its virulence factors, mode of acquisition and long-term prognosis.6 Although it has been isolated from the respiratory tract, the association of B. holmesii nasopharyngeal colonization or infection and bacteremia remains unknown.8 Established, optimal procedures for antibiotic susceptibility testing are needed to effectively guide therapy and to identify resistance patterns for this pathogen. B. holmesii has a predilection for immunocompromised (especially asplenic) hosts but can cause serious disease even in previously healthy individuals. Although no deaths have been reported from endocarditis, some patients required surgical intervention and relapse may occur, especially if a patient has a prosthetic valve. Both adult and pediatric practitioners should be aware of this emerging organism and it should be included in the differential for endocarditis with or without underlying cardiac disease, with or without immunocompromise.
ACKNOWLEDGMENTS The authors would like to thank Dr. Daniel Sundin, PhD, for his help reviewing the article and regarding the microbiology characteristics of B. holmesii. The authors also thank the Spectrum Health library for their assistance in obtaining the necessary resources. REFERENCES 1. Baddour L, Wilson W, Bayer A, et al. Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: endorsed by IDSA. Circulation, J Am Heart Assoc. 2005;111:e394–e434.
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2. Jonckheere S, De Baere T, Schroeyers P, et al. Prosthetic valve endocarditis caused by Bordetella holmesii, an Acinetobacter lookalike. J Med Microbiol. 2012;61(pt 6):874–877. 3. Russell FM, Davis JM, Whipp MJ, et al. Severe Bordetella holmesii infection in a previously healthy adolescent confirmed by gene sequence analysis. Clin Infect Dis. 2001;33:129–130. 4. Clare S, Ahmed T, Singh R, et al. Bordetella holmesii: a rare cause of bacterial endocarditis in a post splenectomy patient. BMJ Case Rep. 2010; Published online May 6, 2010; bcr11.2009.2459. 5. Shepard CW, Daneshvar MI, Kaiser RM, et al. Bordetella holmesii bacteremia: a newly recognized clinical entity among asplenic patients. Clin Infect Dis. 2004;38:799–804. 6. Bush L, Davidson E, Daugherty J. Bordetella holmesii prosthetic valve endocarditis: a case report and review. Infect Dis Clin Pract 2012;20: 248–253. 7. Tang YW, Hopkins MK, Kolbert CP, et al. Bordetella holmesii-like organisms associated with septicemia, endocarditis, and respiratory failure. Clin Infect Dis. 1998;26:389–392. 8. Bassetti M, Nicco E, Giacobbe DR, et al. Bordetella holmesii endocarditis in a patient with systemic lupus erythematous treated with immunosuppressive agents. J Chemother. 2012;24:240–242. 9. Soloaga N, Carrion A, Almuzara M, et al. Bordetella holmesii endocarditis in an asplenic patient. Rev Argent de Microbiol. 2013;45:86–88.
MANAGEMENT OF LATENT TUBERCULOSIS INFECTION IN CHILD CONTACTS OF M ULTIDRUGRESISTANT TUBERCULOSIS Felice C. Adler-Shohet, MD,* Julie Low, MD,† Michael Carson, MS,† Haimanot Girma, MPH,† and Jasjit Singh, MD* Abstract: After exposure to a teacher with multidrug-resistant pulmonary tuberculosis, 31 children developed latent infection. Twenty-six were treated with levofloxacin and pyrazinamide. Twelve required a change in therapy secondary to adverse effects. The most common adverse effects included abdominal pain, arthralgias/myalgias and elevated transaminases. All children reported at least 1 adverse effect. Fifteen children completed treatment. All adverse effects were transient. Key Words: latent tuberculosis, drug resistance, drug therapy, adverse effects Accepted for publication December 23, 2014. From the *Infectious Diseases, Children’s Hospital Orange County, Orange; and † County of Orange Health Care Agency, Santa Ana, CA. The authors have no funding or conflicts of interest to disclose Address for correspondence: Felice C. Adler-Shohet, MD, Infectious Diseases, Children’s Hospital of Orange County, 1201 West La Veta Avenue, Orange, CA 92868–3874. E-mail: [email protected]. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (www.pidj.com). Copyright © 2014 by Lippincott Williams & Wilkins DOI: 10.1097/INF.0000000000000260
M
ultidrug-resistant tuberculosis (MDR-TB) rates are increasing in several parts of the world.1 Children have up to a 50% risk of becoming infected with TB after close contact with an infectious adult, particularly in the home and school setting.2 While the safety and efficacy for treatment of drug-susceptible latent TB infection (LTBI) and TB in children are well described,3 this information is not available for the treatment of MDR-TB and MDR-LTBI. A teacher in California developed MDR-TB exposing dozens of children. This retrospective chart review describes our experience with the contact investigation and treatment of those child contacts. The index case was 4+ acid fast bacilli smear positive and culture grew M. tuberculosis resistant to isoniazid, rifampin
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and ethambutol but susceptible to pyrazinamide (PZA), levofloxacin (LEVO) and ethionamide. The case had contact with dozens of children at a school over a prolonged period within the classroom as well as in other group activities.
MATERIALS AND METHODS The local health department initiated an extensive contact investigation at the school. A contact was defined as a child who spent ≥ 8 cumulative hours in either the same room as the case or the connected classroom. Contacts were screened with a tuberculin skin test (TST). Contacts who were initially TST negative had a second TST performed 8–10 weeks after contact with the case was broken. Contacts with a second negative TST were dismissed from further follow up. All TST-positive children (TST ≥ 5 mm induration) were offered LEVO and PZA in liquid or tablet form for treatment of MDR-LTBI. Parents desiring therapy for their child were offered directly observed therapy (DOT) performed at the school by the health department. On weekends and holidays, parents were provided with the medications for self-administered therapy. During spring and summer vacations and for the subsequent school year, the directly observed therapy program was discontinued; the health department provided parents of child contacts with medication for self-administered therapy on a month-to-month basis. All TST-positive children had a chest X-ray to rule out active disease, and they were followed for 24 months. For the first year after exposure, those on treatment were evaluated monthly either by the local health department or by an Infectious Diseases clinician. Patients were questioned and examined for signs and symptoms of TB disease as well as medication adverse effects. All had monthly testing of transaminases with additional testing if clinically indicated. Chest X-rays were performed every 6 months. Families were advised to call immediately if their child had any possible medication adverse effects or symptoms of active TB disease. Completion of therapy was defined as taking at least 9 months of medication. This research study was approved by the Human Subject Review Committee of the health department. Univariate analysis was performed using PASW Statistics 18 (SPSS, Inc. Quarry Bay, Hong Kong), and statistical significance was defined as P < 0.05. Median number of adverse effects of children who did not complete therapy compared with children who did complete therapy were analyzed using a Mann-Whitney U test for nonnormal data.
RESULTS In the school setting, 118 children had significant contact with the case and were evaluated. No contact had active TB disease at the time of initial evaluation. Thirty-one children (26.3%) had a positive TST, 21 on initial testing and 10 on repeat testing (Fig. 1). Demographic and clinical characteristics of these 31 children are shown in the Table, Supplemental Digital Content 1, http://links.lww.com/INF/B801. Out of 31 children in the teacher’s classroom, where the case spent the majority time, 21 children (67.7%) had a positive TST. The other 10 children with a positive TST had exposures through homework club, daycare, circle time activities or were in an adjoining classroom that was separated from the case’s classroom by a loose, swinging door with a gap at the top. Five children’s parents refused treatment, 26 children (83.9%) started therapy with LEVO and PZA and 15 (57.7%) completed at least 9 months of therapy. Of these 26 children, 12 (46.2%) required an alteration in therapy due to medication adverse effects (Fig. 1). None of the children developed active TB during 24 months of follow up. © 2014 Lippincott Williams & Wilkins
Many biomarkers for KD have been proposed, particularly inflammatory response markers, but no individual biomarker is likely to be diagnostic.9–14 We tested periostin as a possible serum biomarker, because markers of cardiac/vascular injury could be very helpful in differentiating children with KD from children with benign febrile illnesses that do not manifest cardiac pathology. The N-terminal moiety of brain natriuretic peptide (NTproBNP), a cardiac hormone secreted by ventricular cardiomyocytes in response to stress, may also be useful in this regard.9–11,14 It is interesting that in our study, serum periostin levels were increased in some KD patients with echocardiographically normal coronary arteries. It is possible that elevated serum periostin levels in acute KD could result from myocarditis, which is common in the acute phase.15 Our study has several limitations. The target tissue of KD, the coronary artery, is inaccessible to the researcher in living patients, and fortunately, fatalities are unusual. These tissues are available only as autopsy and explanted heart specimens and are thus rare, which accounts for the relatively small sample size of coronary artery tissues in this study. Our labarotory houses 1 of the largest collections of such tissues in North America. We performed immunohistochemistry on KD coronary artery tissues using 2 different commercially available antihuman periostin antibodies, but were unable to determine whether periostin protein was present diffusely in the sections or whether these antibodies resulted in nonspecific staining. We plan to perform ELISA studies on serial acute and convalescent KD sera to evaluate periostin expression levels over time in a future study. In summary, periostin is upregulated in KD coronary tissues, and markedly increased periostin levels are detected in the sera of a subset of KD patients. We propose that a KD biomarker panel be developed and evaluated in a multicenter trial and periostin be included in this panel. The development of diagnostic tools to facilitate rapid therapeutic intervention is essential for this potentially devastating childhood disease.
Periostin in Kawasaki Disease
8. Samsonov MY, Tilz GP, Pisklakov VP, et al. Serum-soluble receptors for tumor necrosis factor-alpha and interleukin-2, and neopterin in acute rheumatic fever. Clin Immunol Immunopathol. 1995;74:31–34. 9. Dahdah N, Siles A, Fournier A, et al. Natriuretic peptide as an adjunctive diagnostic test in the acute phase of Kawasaki disease. Pediatr Cardiol. 2009;30:810–817. 10. Kaneko K, Yoshimura K, Ohashi A, et al. Prediction of the risk of coronary arterial lesions in Kawasaki disease by brain natriuretic peptide. Pediatr Cardiol. 2011;32:1106–1109. 11. Sato YZ, Molkara DP, Daniels LB, et al. Cardiovascular biomarkers in acute Kawasaki disease. Int J Cardiol. 2013;164:58–63. 12. Ling XB, Lau K, Kanegaye JT, et al. A diagnostic algorithm combining clinical and molecular data distinguishes Kawasaki disease from other febrile illnesses. BMC Med. 2011;9:130. 13. Kentsis A, Shulman A, Ahmed S, et al. Urine proteomics for discovery of improved diagnostic markers of Kawasaki disease. EMBO Mol Med. 2013;5:210–220. 14. McNeal-Davidson A, Fournier A, Spigelblatt L, et al. Value of amino-terminal pro B-natriuretic peptide in diagnosing Kawasaki disease. Pediatr Int. 2012;54:627–633. 15. Harada M, Yokouchi Y, Oharaseki T, et al. Histopathological characteristics of myocarditis in acute-phase Kawasaki disease. Histopathology. 2012;61:1156–1167.
BORDETELLA HOLMESII ENDOCARDITIS CASE REPORT AND REVIEW OF LITERATURE
Amy P. Couturier, MD* and Karen Dahl, MD† Abstract: The second case of Bordetella holmesii endocarditis in a pediatric patient is presented. This patient had a prosthetic mitral valve and asplenia. He was successfully treated with 6 weeks of intravenous meropenem. We review all 9 other reported cases of endocarditis and summarize treatment and outcome. Five were immunocompromised and 6 had predisposing cardiac conditions. Key Words: Bordetella holmesii, endocarditis, asplenia, immunocompromise
ACKNOWLEDGMENTS We thank Robin Biggs, Deidre Anderson and Leslie Martin for assistance in identifying and dissecting control coronary artery samples and Moheet Merchant for organization of serum banking. REFERENCES 1. Newburger JW, Takahashi M, Gerber MA, et al.; Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. 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. Pediatrics. 2004;114:1708–1733. 2. Orenstein JM, Shulman ST, Fox LM, et al. Three linked vasculopathic processes characterize Kawasaki disease: a light and transmission electron microscopic study. PLoS One. 2012;7:e38998. 3. Reindel R, Baker SC, Kim KY, et al. Integrins α4 and αM, collagen1A1, and matrix metalloproteinase 7 are upregulated in acute Kawasaki disease vasculopathy. Pediatr Res. 2013;73:332–336. 4. Frangogiannis NG. Matricellular proteins in cardiac adaptation and disease. Physiol Rev. 2012;92:635–688. 5. Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 2008;3:1101–1108. 6. Matsubara T, Furukawa S, Yabuta K. Serum levels of tumor necrosis factor, interleukin 2 receptor, and interferon-gamma in Kawasaki disease involved coronary-artery lesions. Clin Immunol Immunopathol. 1990;56:29–36. 7. Kurane I, Innis BL, Nimmannitya S, et al. Activation of T lymphocytes in dengue virus infections. High levels of soluble interleukin 2 receptor, soluble CD4, soluble CD8, interleukin 2, and interferon-gamma in sera of children with dengue. J Clin Invest. 1991;88:1473–1480.
© 2014 Lippincott Williams & Wilkins
Accepted for publication December 4, 2013. From the *Michigan State University College of Human Medicine; and †Pediatric Infectious Disease Spectrum Health Medical Group, Helen DeVos Children’s Hospital, Michigan State University College of Human Medicine, Grand Rapids, MI. The authors have no funding or conflict of interest to disclose. Address for correspondence: Karen Dahl, MD, Division Chief, Pediatric Infectious Disease, Helen DeVos Children’s Hospital, 100 Michigan St NE Mail Code 177, Grand Rapids, MI 49503. E-mail: [email protected]. Copyright © 2014 by Lippincott Williams & Wilkins DOI: 10.1097/INF.0000000000000234
B
ordetella holmesii is a rare cause of endocarditis reported most often in immunocompromised or asplenic patients. We present the second pediatric case reported in the literature. There have been 9 other cases of B. holmesii endocarditis reported in the literature and 6 had underlying cardiac conditions.
CASE REPORT This 9-year-old male presented with diarrhea, fatigue and low grade fever. His past medical history was significant for anatomical asplenia and congenital heart disease (dextrocardia with a complete atrioventricular canal defect, double outlet right ventricle and pulmonary stenosis), status post closure of atrial septal defect and ventricular septal defect, resection of the infundibular septum, placement of an intraventricular baffle from the left ventricle to www.pidj.com | 661
The Pediatric Infectious Disease Journal • Volume 33, Number 6, June 2014
Couturier and Dahl
TABLE 1. Summary of Documented Bordetella holmesii Endocarditis Cases Authors Tang et al7
Age/Sex 25 years/male
Immunocompromised/ Medical History No (remote history of Hodgkin’s disease)
Echocardiogram Findings
Cardiac History Bicuspid aortic valve
Aortic valve vegetation
Shepard et al5 35 years/male
Unknown
Aortic valvular abscess
Shepard et al5 Clare et al4
Unknown None
Unknown Aortic valve vegetation
Jonckheere et al2
Yes (asplenia, h istory of Hodgkin’s disease) Unknown Unknown 33 years/female Yes (asplenia) 36 years/male
No (chronic alcohol and tobacco use)
Bassetti et al8 48 years/male
Russell et al3
Yes (systemic lupus erythematous, azathropine and prednisone) 14 years/female No
Not mentioned
Unknown Cefotaxime 2 g TID* for 4 weeks Meropenem
Unknown Aortic valve replacement
Aortic valve replacement
Yes
Complete recovery Survived Survived Complete recovery
Aortic valve vegetation
Meropenem 1 g TID
None
Mitral valve prolapse and moderate mitral regurgitation Pulmonary, aortic, and mitral valve vegetations No vegetations initially. At second relapse, aortic valve vegetation No vegetations
Cefotaxime for 6 weeks
None
Pulmonary fibrosis
Ceftriaxone 1 g BID† for 4 weeks
None
Complete recovery
Aortic valve replacement
Bush et al6
80 years/male
Bioprosthetic aortic valve, permanent cardiac pacemaker
Yes (asplenia)
Ceftriaxone 2 g daily for 4 weeks Unknown
Outcome
Aortic valve vegetation and destruction of another leaflet
52 years/female Yes (asplenia, history of Hodgkin’s disease)
Couturier and 9 years/male Dahl
Cardiac Surgical Intervention
Streptococcus bovis endocarditis on post-rheumatic aortic and mitral valves; aortic homograft and mitral mechanical valve Bicuspid aortic valve
Soloaga et al9
No
Antibiotic Therapy
Complex congenital heart disease with mechanical mitral valve
Multiple courses‡
Meropenem 20 mg/ kg/dose TID for 6 weeks
Aortic Complete homograft recovery replaced with mechanical composite valve
Aortic valve replacement after second relapse None
Complete recovery
Right embolic stroke, complete recovery Complete recovery
* TID = every 8 hours. †BID = every 12 hours. ‡Etrapenem, 8 weeks; ceftriaxone, 25 days followed by suppressive oral therapy; ertapenem, 6 weeks.
the aorta, placement of a conduit from the right ventricle to the pulmonary artery and baffling of the left sided inferior vena cava to the right atrium. His most recent cardiac surgery was 6 years ago for prosthetic mitral valve replacement with cardiac baffles. He required multiple procedures for dental caries. He was prescribed warfarin because of his prosthetic valve. Because of his asplenic status, he was prescribed amoxicillin prophylaxis 500 mg daily but he is known to only be partially compliant. All other history was unrelated to his presenting illness. For 3 weeks before admission, the patient had symptoms of diarrhea and required hydration therapy in the emergency department 1 time. Then, he developed a fever of 38.3°C, had decreased appetite, fatigue, sweats and chills and was admitted for evaluation. A blood culture was obtained and therapy with vancomycin and ceftriaxone was initiated. The blood culture remained negative and the patient clinically improved over the course of 4 days. A transthoracic echocardiogram was obtained and did not reveal vegetations or changes from baseline. A transesophageal echocardiogram was considered but not done, as the family did not want to pursue surgical intervention even if there were definitive findings of endocarditis. Culture-negative bacterial endocarditis was suspected due to his underlying
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cardiac disease, history of documented fever and partial adherence with amoxicillin prophylaxis. The family refused further treatment for endocarditis and the patient was discharged with close follow up. The day after discharge, and after 5 days of incubation, the microbiology laboratory reported an unidentified Gram-negative bacterium from the initial blood culture on previous admission. Two subsequent cultures obtained during the hospital admission were sterile. The patient was contacted at home and another blood culture was obtained outpatient but the family refused admission. After 4 days of incubation, this also grew Gram-negative bacilli and the patient was then admitted for treatment of Gram-negative bacteremia and suspected endocarditis. On physical examination, he was well-appearing. His temperature was 38.1°C, respiratory rate of 20 breaths/min, heart rate of 97 beats/min and blood pressure of 107/72 mm Hg. The cardiovascular exam revealed a regular rhythm with a baseline 3/6 systolic ejection murmur loudest at the upper right sternal border and mechanical click. There was no splinter or conjunctival hemorrhages. The remainder of his exam was unremarkable. Laboratory studies revealed a white blood cell count of 16.08 × 103 cells/uL, hemoglobin of 10.1 g/dL and platelets of 378 × 103 cells/uL. A © 2014 Lippincott Williams & Wilkins
The Pediatric Infectious Disease Journal • Volume 33, Number 6, June 2014
complete metabolic panel was significant for calcium of 7.9 mg/ dL, total protein of 5.1 g/dL and an albumin of 2.1 g/dL. A C-reactive protein was 69.7 mg/L (normal < 10 mg/L). Another blood culture was obtained on admission, which was positive after 3 days of incubation. The Pediatric Infectious Disease consultant suspected endocarditis, most likely caused by a HACEK organism (an acronym for fastidious Gram-negative bacilli that are recognized endocarditis pathogens).1 The diagnosis of possible infective endocarditis was based on the modified Duke’s criteria: growth of a potential pathogen on 2 separate blood cultures (1 major); predisposing heart condition and fever (2 minor). He was treated with ceftriaxone, 2 g daily, based on The American Heart Association infective endocarditis guideline.1 The Gram-negative bacterium from his blood culture was sent to the Michigan Department of Community Health and was identified as B. holmesii. Based on the isolate’s minimum inhibitory concentration and a case report of a patient with B. holmesii endocarditis with prosthetic valve who was successfully treated with meropenem,2 antibiotics were changed to meropenem 20 mg/ kg every 8 hours for 6 weeks. The MICs for the patient’s isolate were: ceftriaxone ≥32 ug/mL, meropenem = 0.064 ug/mL and azithromycin = 0.125 ug/mL. A follow-up echocardiogram after completion of 6 weeks of meropenem was unchanged. After meropenem therapy was completed, suppressive therapy with azithromycin was recommended because of the presence of the prosthetic valve and concern for relapse. The patient has been nonadherent with this regimen but after 6 months has remained well.
DISCUSSION A comprehensive PubMed English language literature search of all reported B. holmesii human endocarditis cases was conducted. The terms Bordetella AND holmesii AND endocarditis were used. Additional references from identified articles were reviewed. There are 9 other cases of B. holmesii endocarditis reported in the literature and all are included in our review. We reviewed 1 other pediatric case and 8 adult cases for cardiac history, immunocompromising conditions, echocardiogram findings, treatment and outcome (Table 1). The first pediatric case was presented by Russell et al3. This previously healthy 14-year-old female presented with echocardiogram findings of mitral valve prolapse and moderate mitral regurgitation but no vegetations or pericardial fluid. B. holmesii was isolated repeatedly in blood cultures and she was treated with cefotaxime for 6 weeks for possible endocarditis. Our case report is the second pediatric case of endocarditis which was suspected and treated without evidence of vegetations on echocardiogram. Half of all reported patients with B. holmesii endocarditis were immunocompromised, most commonly due to asplenia. The majority (6 of 10) had predisposing cardiac conditions. It is important to note, however, that 2 patients were previously healthy, without immunocompromise or underlying cardiac disease. At least 5 patients required surgical intervention for valvular replacement and 1 patient with a prosthetic valve relapsed twice after initial presentation. All patients recovered with either medical or medical and surgical treatment and no deaths were reported. B. holmesii was first discovered in 1983 and named in 1995 in honor of Barry Holmes for his contributions in bacteriology. Since then, only case reports have been published. Disease severity ranges from bacteremia to endocarditis requiring surgery and extended hospital stay. Pneumonia, bacteremia with septic shock, © 2014 Lippincott Williams & Wilkins
B. holmesii Endocarditis
cellulitis and suppurative arthritis have also been reported.4 It is evident from the literature that B. holmesii has a predilection for asplenic patients and/or immunocompromised hosts of any age. Shepard et al5 published Centers for Disease Control data for 26 cases of bacteremia with B. holmesii, of which 22 were asplenic. The association not only may be due to immunodeficiency resulting from asplenia that increases the risk for infection but also may be explained by reporting bias of clinicians who are more likely to pursue identification of an isolate in an immunocompromised host.5 Classically, asplenic patients have a predilection for encaspulsated organisms; however, B. holmesii is not known to possess a polysaccharide capsule.6 Defining the microbiologic characteristics has been challenging due to the paucity of isolates and the slow growing nature of the bacterium. B. holmesii is a small, nonmotile, nonhemolytic, catalase-negative, aerobic Gram-negative bacilli that grows best on blood and chocolate agar after at least 48 hours of incubation.6 Its production of a brown soluble pigment when grown on MacConkey agar is specific for B. holmesii.6 Interestingly, Bordetellae oxidize amino acids but generally do not metabolize carbohydrates.6. In some cases, B. holmesii has been confused with Acinetobacter species due to similar microbiologic characteristics; however, Acinetobacter does not produce the brown pigment on MacConkey agar and is catalase positive.6 To best identify the organism, a 16S rRNA gene sequence can determine speciesspecific regions of 20–30 bases and homology sequencing can be compared with known isolates.7 Strain-specific minimum inhibitory concentration should be used for treatment because practice guidelines do not exist for this organism. Endocarditis has been successfully treated with ceftriaxone 2 g daily or meropenem 1–2 g every 8 hours for 4–6 weeks. It should be noted that some isolates are resistant to cephalosporins. Resistance patterns raise a concern for extended spectrum betalactamase production that has not been well-documented but is important to consider in treatment decisions.8 There is a considerable amount of information that is still unknown about B. holmesii especially regarding its virulence factors, mode of acquisition and long-term prognosis.6 Although it has been isolated from the respiratory tract, the association of B. holmesii nasopharyngeal colonization or infection and bacteremia remains unknown.8 Established, optimal procedures for antibiotic susceptibility testing are needed to effectively guide therapy and to identify resistance patterns for this pathogen. B. holmesii has a predilection for immunocompromised (especially asplenic) hosts but can cause serious disease even in previously healthy individuals. Although no deaths have been reported from endocarditis, some patients required surgical intervention and relapse may occur, especially if a patient has a prosthetic valve. Both adult and pediatric practitioners should be aware of this emerging organism and it should be included in the differential for endocarditis with or without underlying cardiac disease, with or without immunocompromise.
ACKNOWLEDGMENTS The authors would like to thank Dr. Daniel Sundin, PhD, for his help reviewing the article and regarding the microbiology characteristics of B. holmesii. The authors also thank the Spectrum Health library for their assistance in obtaining the necessary resources. REFERENCES 1. Baddour L, Wilson W, Bayer A, et al. Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: endorsed by IDSA. Circulation, J Am Heart Assoc. 2005;111:e394–e434.
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2. Jonckheere S, De Baere T, Schroeyers P, et al. Prosthetic valve endocarditis caused by Bordetella holmesii, an Acinetobacter lookalike. J Med Microbiol. 2012;61(pt 6):874–877. 3. Russell FM, Davis JM, Whipp MJ, et al. Severe Bordetella holmesii infection in a previously healthy adolescent confirmed by gene sequence analysis. Clin Infect Dis. 2001;33:129–130. 4. Clare S, Ahmed T, Singh R, et al. Bordetella holmesii: a rare cause of bacterial endocarditis in a post splenectomy patient. BMJ Case Rep. 2010; Published online May 6, 2010; bcr11.2009.2459. 5. Shepard CW, Daneshvar MI, Kaiser RM, et al. Bordetella holmesii bacteremia: a newly recognized clinical entity among asplenic patients. Clin Infect Dis. 2004;38:799–804. 6. Bush L, Davidson E, Daugherty J. Bordetella holmesii prosthetic valve endocarditis: a case report and review. Infect Dis Clin Pract 2012;20: 248–253. 7. Tang YW, Hopkins MK, Kolbert CP, et al. Bordetella holmesii-like organisms associated with septicemia, endocarditis, and respiratory failure. Clin Infect Dis. 1998;26:389–392. 8. Bassetti M, Nicco E, Giacobbe DR, et al. Bordetella holmesii endocarditis in a patient with systemic lupus erythematous treated with immunosuppressive agents. J Chemother. 2012;24:240–242. 9. Soloaga N, Carrion A, Almuzara M, et al. Bordetella holmesii endocarditis in an asplenic patient. Rev Argent de Microbiol. 2013;45:86–88.
MANAGEMENT OF LATENT TUBERCULOSIS INFECTION IN CHILD CONTACTS OF M ULTIDRUGRESISTANT TUBERCULOSIS Felice C. Adler-Shohet, MD,* Julie Low, MD,† Michael Carson, MS,† Haimanot Girma, MPH,† and Jasjit Singh, MD* Abstract: After exposure to a teacher with multidrug-resistant pulmonary tuberculosis, 31 children developed latent infection. Twenty-six were treated with levofloxacin and pyrazinamide. Twelve required a change in therapy secondary to adverse effects. The most common adverse effects included abdominal pain, arthralgias/myalgias and elevated transaminases. All children reported at least 1 adverse effect. Fifteen children completed treatment. All adverse effects were transient. Key Words: latent tuberculosis, drug resistance, drug therapy, adverse effects Accepted for publication December 23, 2014. From the *Infectious Diseases, Children’s Hospital Orange County, Orange; and † County of Orange Health Care Agency, Santa Ana, CA. The authors have no funding or conflicts of interest to disclose Address for correspondence: Felice C. Adler-Shohet, MD, Infectious Diseases, Children’s Hospital of Orange County, 1201 West La Veta Avenue, Orange, CA 92868–3874. E-mail: [email protected]. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (www.pidj.com). Copyright © 2014 by Lippincott Williams & Wilkins DOI: 10.1097/INF.0000000000000260
M
ultidrug-resistant tuberculosis (MDR-TB) rates are increasing in several parts of the world.1 Children have up to a 50% risk of becoming infected with TB after close contact with an infectious adult, particularly in the home and school setting.2 While the safety and efficacy for treatment of drug-susceptible latent TB infection (LTBI) and TB in children are well described,3 this information is not available for the treatment of MDR-TB and MDR-LTBI. A teacher in California developed MDR-TB exposing dozens of children. This retrospective chart review describes our experience with the contact investigation and treatment of those child contacts. The index case was 4+ acid fast bacilli smear positive and culture grew M. tuberculosis resistant to isoniazid, rifampin
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and ethambutol but susceptible to pyrazinamide (PZA), levofloxacin (LEVO) and ethionamide. The case had contact with dozens of children at a school over a prolonged period within the classroom as well as in other group activities.
MATERIALS AND METHODS The local health department initiated an extensive contact investigation at the school. A contact was defined as a child who spent ≥ 8 cumulative hours in either the same room as the case or the connected classroom. Contacts were screened with a tuberculin skin test (TST). Contacts who were initially TST negative had a second TST performed 8–10 weeks after contact with the case was broken. Contacts with a second negative TST were dismissed from further follow up. All TST-positive children (TST ≥ 5 mm induration) were offered LEVO and PZA in liquid or tablet form for treatment of MDR-LTBI. Parents desiring therapy for their child were offered directly observed therapy (DOT) performed at the school by the health department. On weekends and holidays, parents were provided with the medications for self-administered therapy. During spring and summer vacations and for the subsequent school year, the directly observed therapy program was discontinued; the health department provided parents of child contacts with medication for self-administered therapy on a month-to-month basis. All TST-positive children had a chest X-ray to rule out active disease, and they were followed for 24 months. For the first year after exposure, those on treatment were evaluated monthly either by the local health department or by an Infectious Diseases clinician. Patients were questioned and examined for signs and symptoms of TB disease as well as medication adverse effects. All had monthly testing of transaminases with additional testing if clinically indicated. Chest X-rays were performed every 6 months. Families were advised to call immediately if their child had any possible medication adverse effects or symptoms of active TB disease. Completion of therapy was defined as taking at least 9 months of medication. This research study was approved by the Human Subject Review Committee of the health department. Univariate analysis was performed using PASW Statistics 18 (SPSS, Inc. Quarry Bay, Hong Kong), and statistical significance was defined as P < 0.05. Median number of adverse effects of children who did not complete therapy compared with children who did complete therapy were analyzed using a Mann-Whitney U test for nonnormal data.
RESULTS In the school setting, 118 children had significant contact with the case and were evaluated. No contact had active TB disease at the time of initial evaluation. Thirty-one children (26.3%) had a positive TST, 21 on initial testing and 10 on repeat testing (Fig. 1). Demographic and clinical characteristics of these 31 children are shown in the Table, Supplemental Digital Content 1, http://links.lww.com/INF/B801. Out of 31 children in the teacher’s classroom, where the case spent the majority time, 21 children (67.7%) had a positive TST. The other 10 children with a positive TST had exposures through homework club, daycare, circle time activities or were in an adjoining classroom that was separated from the case’s classroom by a loose, swinging door with a gap at the top. Five children’s parents refused treatment, 26 children (83.9%) started therapy with LEVO and PZA and 15 (57.7%) completed at least 9 months of therapy. Of these 26 children, 12 (46.2%) required an alteration in therapy due to medication adverse effects (Fig. 1). None of the children developed active TB during 24 months of follow up. © 2014 Lippincott Williams & Wilkins
