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Tuberculous lymphadenitis of the head and neck in Canadian children: Experience from a low-burden region
International Journal of Pediatric Otorhinolaryngology 91 (2016) 11e14
Contents lists available at ScienceDirect
International Journal of Pediatric Otorhinolaryngology journal homepage: http://www.ijporlonline.com/
Tuberculous lymphadenitis of the head and neck in Canadian children: Experience from a low-burden region Jason J. Xu a, *, 1, Shazia Peer a, 1, Blake C. Papsin a, Ian Kitai b, 2, Evan J. Propst a, 2 a b
Department of Otolaryngology e Head & Neck Surgery, University of Toronto, 190 Elizabeth St., Rm 3S-438, Toronto, ON, M5G 2N2, Canada Division of Infectious Diseases, Department of Paediatrics, Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada
a r t i c l e i n f o
a b s t r a c t
Article history: Received 22 May 2016 Received in revised form 24 September 2016 Accepted 26 September 2016 Available online 28 September 2016
Background: Children are more likely than adults to develop extra-pulmonary tuberculosis (EPTB), which often presents as cervical lymphadenopathy. The role of surgery in management is uncertain. We reviewed all head and neck EPTB cases presenting to our tertiary care pediatric institution over a twelveyear period. Methods: All children 18 years of age and younger with EPTB involving the head and neck were included. We recorded clinical data and age at diagnosis, birth country, BCG vaccination status, as well as radiographic, surgical, histological, and microbiological results. Results: All 16 patients presented with cervical lymphadenopathy. Fourteen were born outside of Canada in TB endemic areas and all had foreign-born parents. Diagnosis was confirmed microbiologically from lymph node biopsies in 14 cases. Multi-drug resistant TB was identified in two cases: both had previous excisional node biopsies that had not been cultured. Two patients had culture negative suppuration despite adequate anti-tuberculous treatment that required surgery for cure. Conclusion: Ongoing suppuration despite appropriate drug therapy is seen in a minority of patients. We found that excisional lymph node biopsy of diseased cervical lymph nodes is diagnostic, and also therapeutic in some cases with ongoing suppuration despite appropriate drug therapy. Mycobacterial culture of lymph nodes is important for diagnosis and determination of drug resistance patterns. © 2016 Elsevier Ireland Ltd. All rights reserved.
Keywords: Tuberculosis Children Extra-pulmonary Head and neck Scrofula
1. Introduction Tuberculosis (TB) is the second most common infectious cause of death worldwide [1]. In Canada, the majority of reported cases occur in immigrants and refugees born in high TB-incident areas [2]. Tuberculosis in children is often a sentinel event implying transmission of infection from an adult with pulmonary TB [2,3]. Children have higher rates of extra-pulmonary TB (EPTB) than adults [4]. Most cases manifest as lymphadenopathy, which is a nonspecific finding. This makes diagnosis challenging and often delayed [5]. Cervical lymph nodes are most commonly involved and can be the sole manifestation of tuberculosis in 25e35% of cases [5]. Persistent lymphadenitis may result in abscess and chronic sinus formation e termed scrofula e and may persist despite appropriate
* Corresponding author. E-mail addresses: [email protected] (J.J. Xu), [email protected] (I. Kitai). 1 Both authors contributed equally. 2 Both authors contributed equally. http://dx.doi.org/10.1016/j.ijporl.2016.09.035 0165-5876/© 2016 Elsevier Ireland Ltd. All rights reserved.
anti-tuberculous treatment [6]. In adult patients, some authorities recommend excisional surgery as the primary approach for diagnosis and cure [6]. In low burden countries, clinicians should be cognizant of this rare disease to ensure prompt diagnosis and optimal management [7]. There are many published series of adults with head and neck TB from TB-endemic areas [8e11], but there is little data about this condition in children from low-burden countries such as Canada, where the incidence of TB is less than 5 per 100,000 [12]. In contrast, clinicians are more likely to encounter nontuberculous mycobacteria lymphadenitis in the pediatric population, which has an incidence of 107 per 100,000 [13]. The aim of this study was to review our experience with TB of the head and neck at a large pediatric tertiary-care center in a low-burden region to learn more about this rare condition in order to improve diagnosis and treatment. 2. Methods We reviewed all patients with TB younger than 18 years of age
12
J.J. Xu et al. / International Journal of Pediatric Otorhinolaryngology 91 (2016) 11e14
managed by the Tuberculosis program at The Hospital for Sick Children in Toronto, Canada, from January 1, 2002 to June 1, 2014. Inclusion criteria were the presence of significant cervical lymphadenopathy or other disease of the head and neck, and a positive culture or Nucleic Acid Amplification Test (NAAT) for Mycobacterium tuberculosis from any site. Patient information was obtained from patient records and a prospectively populated database obtained at entry to our TB clinic. We recorded: 1) date of birth; 2) age at diagnosis; 3) place of birth of patient and parents; 4) duration of time living in Canada prior to diagnosis; 5) BCG (Bacillus Calmrin) vaccination status; 6) chest x-ray (CXR) findings; 7) etteeGue tuberculin skin test (TST) results; 8) surgical, histopathological and microbiological reports. This study was approved by The Hospital for Sick Children Research Ethics Board. 3. Results Sixteen cases of EPTB of the head and neck were included. All patients presented with symptomatic cervical lymphadenopathy and one child presented with concurrent meningitis. All children were otherwise healthy and none had known exposure to TB. HIV (human immunodeficiency virus) screening was performed for 10 children and was negative in all cases. No cases of sinus, ear, or laryngeal TB were identified in our review. 3.1. Demographics The mean (standard deviation, SD) age at time of diagnosis was 13.4 (4.0) years (range 1e17 years). Fifteen (94%) children were ten years of age or older. Fourteen (88%) children were born outside of Canada. Six (38%) of these were born in South Asia, 4 (25%) in Africa, and 4 (25%) in East Asia. The mean (SD) duration in Canada prior to diagnosis was 4.46 (3.4) years (range 0.1e10 years). Nine children (56%) lived in Canada for 5 years or less before being diagnosed. Of the 2 (12%) Canadian-born children, 1 was diagnosed at 1 year of age and the other at 17 years of age. The one-year-old child presented with meningitis in addition to cervical lymphadenopathy. Both had parents born in TB-endemic countries. BCG vaccination was documented in nine (56%) children. 3.2. Diagnostic tests Results of diagnostic testing are detailed in Table 1. Abnormal chest radiography was present in 7 children: 4 with mediastinal or hilar lymphadenopathy, 2 with pulmonary infiltrates, and 1 with a small pulmonary nodule. Interferon-gamma release assays are not routinely used at our institution and were not used for any case in this series. Spoligotyping is performed but the results are collected for a provincial database and were not available for this review. 3.3. Biopsy results Tissue biopsies were obtained from either cervical (94%) or parotid lymph nodes (6%). Twelve children (75%) had excisional biopsies, 3 (19%) had incisional biopsies, and 1 (6%) had a core
Table 1 Ancillary test results.
needle biopsy. The type of biopsy performed was determined by the otolaryngologist-head & neck surgeon or general surgeon involved. Biopsy results are detailed in Table 2. Two patients had nodes that were culture negative but showed histologic evidence of granulomatous inflammation. For one of these patients, TB was diagnosed based on a concurrent positive NAAT of induced sputum. In the other patient, culture-positive drug sensitive TB had been diagnosed 2 years previously and the patient was treated with 9 months of anti-TB therapy at that time; the lymphadenitis was thought to be a late granulomatous reaction. Twelve of the 14 (86%) culture-positive specimens were sensitive to ethambutol, isoniazid (INH), rifampicin and pyrazinamide. Two (12%) were multi-drug resistant (MDR), implying resistance to both INH and rifampicin (Table 3). Both of these patients had prior excision of cervical nodes at community hospitals with negative TB cultures, but received empirical TB treatment based on histology results and strongly positive TST. They both were well following treatment for approximately 1 year before presenting to our institution with recurrent lymphadenopathy. Subsequent excisional biopsy cultures were both positive for the MDR organism. 3.4. Treatment and follow-up Fifteen out of the 16 patients received anti-tuberculous treatment. The one patient thought to have had a late granulomatous reaction had no further therapy after lymph node biopsy. One patient emigrated 3 months after starting treatment, with appropriate arrangements made for ongoing care. For the remaining patients, the mean (SD) follow-up duration was 24.4 (13.7) months (range 11e53 months). There was no recurrence of disease in any patients including those with MDR disease. All 12 patients with a positive node culture for drug sensitive TB and the patient with a negative node culture but NAAT-positive sputum were treated with a combination of ethambutol, INH, rifampicin and pyrazinamide based on standard regimens. Treatment was directly observed by municipal public health departments. Excluding the one patient who emigrated, the treatment duration for the remaining cases was typically 12 months (mean (SD) ¼ 12.5 (4.1)), however duration ranged from 6 to 24 months. One patient who received a total of 24 months of treatment had ongoing suppuration that developed 1 year after initiating treatment. Four of these 13 patients (31%) experienced significant medical adverse effects (3 hepatotoxicity, 2 gastrointestinal intolerance) that required temporary cessation of medication or admission to hospital. Therapy was successfully completed in all. The two patients with MDR TB received over 18 months of therapy (Table 3), which included a four-month course of amikacin, and a fluoroquinolone (either moxifloxacin or ofloxacin). One child experienced significant vestibulotoxicity secondary to amikacin, which was replaced with cycloserine and clofazamine. The same child also developed hypothyroidism and iron-deficiency anemia. Both MDR cases also experienced significant gastrointestinal intolerance. Two children with drug-sensitive TB (13%) developed a draining
Table 2 Lymph node biopsy results.
Ancillary test
N (percentage)
Biopsy results
N (percentage)
Positive tuberculin skin test (TST) Abnormal chest x-ray Positive sputum culture Positive gastric aspirate culture HIV test
10/10 (100%) 7/16 (44%) 6/10 (60%) 5/6 (83%) 0/10 (0%)
Histopathology: necrotizing granulomatous inflammation Positive node culture Positive acid-fast bacillus stain Positive nucleic acid amplification test (NAAT) MDR TB
14/14 (100%) 14/16 (87.5%) 3/13 (23.1%) 7/8 (87.5%) 2/16 (12.5%)
J.J. Xu et al. / International Journal of Pediatric Otorhinolaryngology 91 (2016) 11e14
13
Table 3 Multi-drug resistant cases. Case
Age
Presentation
Resistance
Treatment
Complications
Follow up (Months)
Outcome
1
13
Neck and supraclavicular nodes
INH, RMP, PZA, EMB, SM
PAS, Moxifloxacin, cycloserine, clofazamine
53
Cured
2
9
Multiple parotid nodes
INH, RMP, PZA
PAS, amikacin, ofloxicin, EMB
Vestibulotoxicity, hypothyroidism, Fe-deficiency anemia, GI intolerance GI intolerance
37
Cured
EMB ¼ ethambutol; INH ¼ isoniazid; PZA ¼ pyrazinamide; RMP ¼ rifampicin; SM ¼ streptomycin; PAS ¼ 4-aminosalicylic acid.
sinus during therapy. One child developed persistent enlargement and suppuration of adjacent nodes despite 24 months of treatment, and subsequently underwent surgical excision of the sinus and underlying nodes which cured the process. No TB organisms were cultured or detected from the excised specimen. The other child developed the sinus 2 months after initiating treatment. This case was attributed to a paradoxical reaction (defined as clinical worsening of TB lesions while on treatment) [10], and a 10 day course of systemic steroids significantly reduced the nodal size and drainage symptoms.
one year after initiating medical therapy. Similar ongoing suppuration is seen in about 20% of adult patients [6]. This study has several limitations including the retrospective design, the fact that it is hospital based, and the small number of patients. The cases described were only those treated at our tertiary level center and may not be representative of all cases in the region. Nonetheless, this is one of the largest published series of TB lymphadenitis from a low burden country.
4. Discussion
We found head and neck TB usually presents as persistent lymphadenopathy in older children who are foreign-born, or have a foreign born parent. Lymph node biopsy is necessary for diagnosis with the tissue sample sent for microbiological culture, drug sensitivities, and histopathology. Our experience suggests that empiric treatment without knowing drug susceptibilities may lead to drug resistance, and that excisional biopsy is preferred because it is therapeutic and prevents creation of a persistently draining sinus.
Tuberculosis presenting in the head and neck is rare in Canadian children, even though EPTB is more common in Canadian adolescents than isolated pulmonary disease [14]. We identified 16 cases of head and neck EPTB presenting or referred to our tertiary care pediatric hospital over twelve years. All presented as cervical lymphadenopathy, which is similar to the high rates of lymphadenopathy reported in adults and TB endemic areas [8e11]. The majority of patients were greater than 10 years of age at presentation. Almost all patients were born in TB endemic areas or travelled to these areas, and all had a foreign-born parent. A history of having received BCG vaccination was not protective against TB. HIV was not a risk factor for EPTB in children. Surgical biopsy of lymphadenopathy plays an important role in the diagnosis of EPTB. In 37% of patients, biopsy was required to establish a diagnosis of TB because none of the other tests (i.e. CXR, sputum culture, or gastric aspirate) were positive. In the other patients with positive TB cultures from other sites, the lymph node biopsy was helpful for confirmation of EPTB. While the TST was the only test that was positive in all 10 patients tested, it does not diagnose active disease and can be positive following prior TB infection or BCG vaccination [15]. Lymph node biopsy alone was diagnostic of TB in all but two patients. In one patient, even though the diagnosis of TB was eventually made on sputum NAAT, the lymph node biopsy was still useful to exclude other diagnoses such as atypical mycobacterial infections or lymphoma, which can present in a similar fashion. For the other patient, there was a prior history of previously treated mediastinal EPTB, and cervical node excision was necessary to rule out recurrence of active disease. Biopsies in our series were obtained via excisional, incisional and core needle techniques. These techniques were chosen over fine needle aspiration as they can rule out other possible etiologies of chronic lymphadenopathy that are more prevalent at our institution, such as lymphoma. The diagnostic yield of the biopsy was not affected by technique used, however, only one core needle biopsy was performed. Incisional and core needle techniques are generally not advised if there is clinical suspicion for tuberculosis or atypical mycobacterial lymphadenopathy because there is a high risk of sinus tract formation from the entry site [16]. Furthermore, excisional biopsy is therapeutic for atypical mycobacterial lymphadenitis, and may similarly be curative for focal EPTB, as it was for one patient in our series who developed multiple draining sinuses
5. Conclusion
Funding source This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Potential conflicts of interest The authors have no conflicts of interest relevant to this article to disclose. References [1] World Health Organization Global Tuberculosis Report, 2014. Published 2014. Accessed March 1, 2015, http://apps.who.int/iris/bitstream/10665/137094/1/ 9789241564809_eng.pdf. [2] C. Greenaway, A. Sandoe, B. Vissandjee, et al., Tuberculosis: evidence review for newly arriving immigrants and refugees, CMAJ 183 (12) (2011) E939eE951, http://dx.doi.org/10.1503/cmaj.090302. [3] I. Kitai, S.K. Morris, Encounters with an old foe: childhood tuberculosis in Canada, Paediatr. Child. Heal 19 (2) (2014) 89e90. [4] X.T. Ussery, S.E. Valway, M. McKenna, G.M. Cauthen, E. McCray, I.M. Onorato, Epidemiology of tuberculosis among children in the United States: 1985 to 1994, Pediatr. Infect. Dis. J. 15 (8) (1996) 697e704. [5] Angela Houston DCM Extrapulmonary tuberculosis, Med. Baltim. 42 (1) (2014) 18e22. [6] J.M. Fontanilla, A. Barnes, C.F. von Reyn, Current diagnosis and management of peripheral tuberculous lymphadenitis, Clin. Infect. Dis. 53 (6) (2011) 555e562, http://dx.doi.org/10.1093/cid/cir454. [7] A. Kam, L. Ford-Jones, P. Malloy, K. Khan, I. Kitai, Active tuberculosis among adolescents in toronto, Canada: clinical features and delays in diagnosis, Pediatr. Infect. Dis. J. 26 (4) (2007) 355e356, http://dx.doi.org/10.1097/ 01.inf.0000258700.86040.b6. [8] K. Menon, C. Bem, D. Gouldesbrough, D.R. Strachan, A clinical review of 128 cases of head and neck tuberculosis presenting over a 10-year period in Bradford, UK, J. Laryngol. Otol. 121 (4) (2007) 362e368, http://dx.doi.org/ 10.1017/S0022215106002507. [9] K.C. Prasad, S. Sreedharan, Y. Chakravarthy, S.C. Prasad, Tuberculosis in the head and neck: experience in India, J. Laryngol. Otol. 121 (10) (2007) 979e985, http://dx.doi.org/10.1017/S0022215107006913. [10] C.M. Chiesa Estomba, F.A. Betances Reinoso, T. Rivera Schmitz, C.C. Ossa lez Corte s, C. Santidrian Hidalgo, Head and neck tuberEcheverri, M.J. Gonza culosis: 6-year retrospective study, Acta Otorrinolaringol. Esp. (January 2015),
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http://dx.doi.org/10.1016/j.otorri.2014.11.003. [11] Fazal-I-wahid, Habib-Ur-Rehman, I. Ahmad, Extrapulmonary tuberculosis in patients with cervical lymphadenopathy, J. Pak. Med. Assoc. 63 (9) (2013) 1094e1097. [12] Public Health Agency of Canada, Tuberculosis in Canada 2014 e Pre-release, 2016. [13] V. Tremblay, T. Ayad, A. Lapointe, et al., Nontuberculous mycobacterial cervicofacial adenitis in children: epidemiologic study, J. Otolaryngol. - Head. Neck Surg. 37 (5) (2008) 616e622. [14] W. Phongsamart, I. Kitai, M. Gardam, J. Wang, K. Khan, A population-based
study of tuberculosis in children and adolescents in Ontario, Pediatr. Infect. Dis. J. 28 (5) (2009) 416e419, http://dx.doi.org/10.1097/ INF.0b013e3181920d4d. [15] M. Pai, C.M. Denkinger, S.V. Kik, et al., Gamma interferon release assays for detection of Mycobacterium tuberculosis infection, Clin. Microbiol. Rev. 27 (1) (2014) 3e20, http://dx.doi.org/10.1128/CMR.00034-13. [16] C.A. Scott, S.H. Atkinson, A. Sodha, et al., Management of lymphadenitis due to non-tuberculous mycobacterial infection in children, Pediatr. Surg. Int. 28 (5) (2012) 461e466, http://dx.doi.org/10.1007/s00383-012-3068-8.
Contents lists available at ScienceDirect
International Journal of Pediatric Otorhinolaryngology journal homepage: http://www.ijporlonline.com/
Tuberculous lymphadenitis of the head and neck in Canadian children: Experience from a low-burden region Jason J. Xu a, *, 1, Shazia Peer a, 1, Blake C. Papsin a, Ian Kitai b, 2, Evan J. Propst a, 2 a b
Department of Otolaryngology e Head & Neck Surgery, University of Toronto, 190 Elizabeth St., Rm 3S-438, Toronto, ON, M5G 2N2, Canada Division of Infectious Diseases, Department of Paediatrics, Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada
a r t i c l e i n f o
a b s t r a c t
Article history: Received 22 May 2016 Received in revised form 24 September 2016 Accepted 26 September 2016 Available online 28 September 2016
Background: Children are more likely than adults to develop extra-pulmonary tuberculosis (EPTB), which often presents as cervical lymphadenopathy. The role of surgery in management is uncertain. We reviewed all head and neck EPTB cases presenting to our tertiary care pediatric institution over a twelveyear period. Methods: All children 18 years of age and younger with EPTB involving the head and neck were included. We recorded clinical data and age at diagnosis, birth country, BCG vaccination status, as well as radiographic, surgical, histological, and microbiological results. Results: All 16 patients presented with cervical lymphadenopathy. Fourteen were born outside of Canada in TB endemic areas and all had foreign-born parents. Diagnosis was confirmed microbiologically from lymph node biopsies in 14 cases. Multi-drug resistant TB was identified in two cases: both had previous excisional node biopsies that had not been cultured. Two patients had culture negative suppuration despite adequate anti-tuberculous treatment that required surgery for cure. Conclusion: Ongoing suppuration despite appropriate drug therapy is seen in a minority of patients. We found that excisional lymph node biopsy of diseased cervical lymph nodes is diagnostic, and also therapeutic in some cases with ongoing suppuration despite appropriate drug therapy. Mycobacterial culture of lymph nodes is important for diagnosis and determination of drug resistance patterns. © 2016 Elsevier Ireland Ltd. All rights reserved.
Keywords: Tuberculosis Children Extra-pulmonary Head and neck Scrofula
1. Introduction Tuberculosis (TB) is the second most common infectious cause of death worldwide [1]. In Canada, the majority of reported cases occur in immigrants and refugees born in high TB-incident areas [2]. Tuberculosis in children is often a sentinel event implying transmission of infection from an adult with pulmonary TB [2,3]. Children have higher rates of extra-pulmonary TB (EPTB) than adults [4]. Most cases manifest as lymphadenopathy, which is a nonspecific finding. This makes diagnosis challenging and often delayed [5]. Cervical lymph nodes are most commonly involved and can be the sole manifestation of tuberculosis in 25e35% of cases [5]. Persistent lymphadenitis may result in abscess and chronic sinus formation e termed scrofula e and may persist despite appropriate
* Corresponding author. E-mail addresses: [email protected] (J.J. Xu), [email protected] (I. Kitai). 1 Both authors contributed equally. 2 Both authors contributed equally. http://dx.doi.org/10.1016/j.ijporl.2016.09.035 0165-5876/© 2016 Elsevier Ireland Ltd. All rights reserved.
anti-tuberculous treatment [6]. In adult patients, some authorities recommend excisional surgery as the primary approach for diagnosis and cure [6]. In low burden countries, clinicians should be cognizant of this rare disease to ensure prompt diagnosis and optimal management [7]. There are many published series of adults with head and neck TB from TB-endemic areas [8e11], but there is little data about this condition in children from low-burden countries such as Canada, where the incidence of TB is less than 5 per 100,000 [12]. In contrast, clinicians are more likely to encounter nontuberculous mycobacteria lymphadenitis in the pediatric population, which has an incidence of 107 per 100,000 [13]. The aim of this study was to review our experience with TB of the head and neck at a large pediatric tertiary-care center in a low-burden region to learn more about this rare condition in order to improve diagnosis and treatment. 2. Methods We reviewed all patients with TB younger than 18 years of age
12
J.J. Xu et al. / International Journal of Pediatric Otorhinolaryngology 91 (2016) 11e14
managed by the Tuberculosis program at The Hospital for Sick Children in Toronto, Canada, from January 1, 2002 to June 1, 2014. Inclusion criteria were the presence of significant cervical lymphadenopathy or other disease of the head and neck, and a positive culture or Nucleic Acid Amplification Test (NAAT) for Mycobacterium tuberculosis from any site. Patient information was obtained from patient records and a prospectively populated database obtained at entry to our TB clinic. We recorded: 1) date of birth; 2) age at diagnosis; 3) place of birth of patient and parents; 4) duration of time living in Canada prior to diagnosis; 5) BCG (Bacillus Calmrin) vaccination status; 6) chest x-ray (CXR) findings; 7) etteeGue tuberculin skin test (TST) results; 8) surgical, histopathological and microbiological reports. This study was approved by The Hospital for Sick Children Research Ethics Board. 3. Results Sixteen cases of EPTB of the head and neck were included. All patients presented with symptomatic cervical lymphadenopathy and one child presented with concurrent meningitis. All children were otherwise healthy and none had known exposure to TB. HIV (human immunodeficiency virus) screening was performed for 10 children and was negative in all cases. No cases of sinus, ear, or laryngeal TB were identified in our review. 3.1. Demographics The mean (standard deviation, SD) age at time of diagnosis was 13.4 (4.0) years (range 1e17 years). Fifteen (94%) children were ten years of age or older. Fourteen (88%) children were born outside of Canada. Six (38%) of these were born in South Asia, 4 (25%) in Africa, and 4 (25%) in East Asia. The mean (SD) duration in Canada prior to diagnosis was 4.46 (3.4) years (range 0.1e10 years). Nine children (56%) lived in Canada for 5 years or less before being diagnosed. Of the 2 (12%) Canadian-born children, 1 was diagnosed at 1 year of age and the other at 17 years of age. The one-year-old child presented with meningitis in addition to cervical lymphadenopathy. Both had parents born in TB-endemic countries. BCG vaccination was documented in nine (56%) children. 3.2. Diagnostic tests Results of diagnostic testing are detailed in Table 1. Abnormal chest radiography was present in 7 children: 4 with mediastinal or hilar lymphadenopathy, 2 with pulmonary infiltrates, and 1 with a small pulmonary nodule. Interferon-gamma release assays are not routinely used at our institution and were not used for any case in this series. Spoligotyping is performed but the results are collected for a provincial database and were not available for this review. 3.3. Biopsy results Tissue biopsies were obtained from either cervical (94%) or parotid lymph nodes (6%). Twelve children (75%) had excisional biopsies, 3 (19%) had incisional biopsies, and 1 (6%) had a core
Table 1 Ancillary test results.
needle biopsy. The type of biopsy performed was determined by the otolaryngologist-head & neck surgeon or general surgeon involved. Biopsy results are detailed in Table 2. Two patients had nodes that were culture negative but showed histologic evidence of granulomatous inflammation. For one of these patients, TB was diagnosed based on a concurrent positive NAAT of induced sputum. In the other patient, culture-positive drug sensitive TB had been diagnosed 2 years previously and the patient was treated with 9 months of anti-TB therapy at that time; the lymphadenitis was thought to be a late granulomatous reaction. Twelve of the 14 (86%) culture-positive specimens were sensitive to ethambutol, isoniazid (INH), rifampicin and pyrazinamide. Two (12%) were multi-drug resistant (MDR), implying resistance to both INH and rifampicin (Table 3). Both of these patients had prior excision of cervical nodes at community hospitals with negative TB cultures, but received empirical TB treatment based on histology results and strongly positive TST. They both were well following treatment for approximately 1 year before presenting to our institution with recurrent lymphadenopathy. Subsequent excisional biopsy cultures were both positive for the MDR organism. 3.4. Treatment and follow-up Fifteen out of the 16 patients received anti-tuberculous treatment. The one patient thought to have had a late granulomatous reaction had no further therapy after lymph node biopsy. One patient emigrated 3 months after starting treatment, with appropriate arrangements made for ongoing care. For the remaining patients, the mean (SD) follow-up duration was 24.4 (13.7) months (range 11e53 months). There was no recurrence of disease in any patients including those with MDR disease. All 12 patients with a positive node culture for drug sensitive TB and the patient with a negative node culture but NAAT-positive sputum were treated with a combination of ethambutol, INH, rifampicin and pyrazinamide based on standard regimens. Treatment was directly observed by municipal public health departments. Excluding the one patient who emigrated, the treatment duration for the remaining cases was typically 12 months (mean (SD) ¼ 12.5 (4.1)), however duration ranged from 6 to 24 months. One patient who received a total of 24 months of treatment had ongoing suppuration that developed 1 year after initiating treatment. Four of these 13 patients (31%) experienced significant medical adverse effects (3 hepatotoxicity, 2 gastrointestinal intolerance) that required temporary cessation of medication or admission to hospital. Therapy was successfully completed in all. The two patients with MDR TB received over 18 months of therapy (Table 3), which included a four-month course of amikacin, and a fluoroquinolone (either moxifloxacin or ofloxacin). One child experienced significant vestibulotoxicity secondary to amikacin, which was replaced with cycloserine and clofazamine. The same child also developed hypothyroidism and iron-deficiency anemia. Both MDR cases also experienced significant gastrointestinal intolerance. Two children with drug-sensitive TB (13%) developed a draining
Table 2 Lymph node biopsy results.
Ancillary test
N (percentage)
Biopsy results
N (percentage)
Positive tuberculin skin test (TST) Abnormal chest x-ray Positive sputum culture Positive gastric aspirate culture HIV test
10/10 (100%) 7/16 (44%) 6/10 (60%) 5/6 (83%) 0/10 (0%)
Histopathology: necrotizing granulomatous inflammation Positive node culture Positive acid-fast bacillus stain Positive nucleic acid amplification test (NAAT) MDR TB
14/14 (100%) 14/16 (87.5%) 3/13 (23.1%) 7/8 (87.5%) 2/16 (12.5%)
J.J. Xu et al. / International Journal of Pediatric Otorhinolaryngology 91 (2016) 11e14
13
Table 3 Multi-drug resistant cases. Case
Age
Presentation
Resistance
Treatment
Complications
Follow up (Months)
Outcome
1
13
Neck and supraclavicular nodes
INH, RMP, PZA, EMB, SM
PAS, Moxifloxacin, cycloserine, clofazamine
53
Cured
2
9
Multiple parotid nodes
INH, RMP, PZA
PAS, amikacin, ofloxicin, EMB
Vestibulotoxicity, hypothyroidism, Fe-deficiency anemia, GI intolerance GI intolerance
37
Cured
EMB ¼ ethambutol; INH ¼ isoniazid; PZA ¼ pyrazinamide; RMP ¼ rifampicin; SM ¼ streptomycin; PAS ¼ 4-aminosalicylic acid.
sinus during therapy. One child developed persistent enlargement and suppuration of adjacent nodes despite 24 months of treatment, and subsequently underwent surgical excision of the sinus and underlying nodes which cured the process. No TB organisms were cultured or detected from the excised specimen. The other child developed the sinus 2 months after initiating treatment. This case was attributed to a paradoxical reaction (defined as clinical worsening of TB lesions while on treatment) [10], and a 10 day course of systemic steroids significantly reduced the nodal size and drainage symptoms.
one year after initiating medical therapy. Similar ongoing suppuration is seen in about 20% of adult patients [6]. This study has several limitations including the retrospective design, the fact that it is hospital based, and the small number of patients. The cases described were only those treated at our tertiary level center and may not be representative of all cases in the region. Nonetheless, this is one of the largest published series of TB lymphadenitis from a low burden country.
4. Discussion
We found head and neck TB usually presents as persistent lymphadenopathy in older children who are foreign-born, or have a foreign born parent. Lymph node biopsy is necessary for diagnosis with the tissue sample sent for microbiological culture, drug sensitivities, and histopathology. Our experience suggests that empiric treatment without knowing drug susceptibilities may lead to drug resistance, and that excisional biopsy is preferred because it is therapeutic and prevents creation of a persistently draining sinus.
Tuberculosis presenting in the head and neck is rare in Canadian children, even though EPTB is more common in Canadian adolescents than isolated pulmonary disease [14]. We identified 16 cases of head and neck EPTB presenting or referred to our tertiary care pediatric hospital over twelve years. All presented as cervical lymphadenopathy, which is similar to the high rates of lymphadenopathy reported in adults and TB endemic areas [8e11]. The majority of patients were greater than 10 years of age at presentation. Almost all patients were born in TB endemic areas or travelled to these areas, and all had a foreign-born parent. A history of having received BCG vaccination was not protective against TB. HIV was not a risk factor for EPTB in children. Surgical biopsy of lymphadenopathy plays an important role in the diagnosis of EPTB. In 37% of patients, biopsy was required to establish a diagnosis of TB because none of the other tests (i.e. CXR, sputum culture, or gastric aspirate) were positive. In the other patients with positive TB cultures from other sites, the lymph node biopsy was helpful for confirmation of EPTB. While the TST was the only test that was positive in all 10 patients tested, it does not diagnose active disease and can be positive following prior TB infection or BCG vaccination [15]. Lymph node biopsy alone was diagnostic of TB in all but two patients. In one patient, even though the diagnosis of TB was eventually made on sputum NAAT, the lymph node biopsy was still useful to exclude other diagnoses such as atypical mycobacterial infections or lymphoma, which can present in a similar fashion. For the other patient, there was a prior history of previously treated mediastinal EPTB, and cervical node excision was necessary to rule out recurrence of active disease. Biopsies in our series were obtained via excisional, incisional and core needle techniques. These techniques were chosen over fine needle aspiration as they can rule out other possible etiologies of chronic lymphadenopathy that are more prevalent at our institution, such as lymphoma. The diagnostic yield of the biopsy was not affected by technique used, however, only one core needle biopsy was performed. Incisional and core needle techniques are generally not advised if there is clinical suspicion for tuberculosis or atypical mycobacterial lymphadenopathy because there is a high risk of sinus tract formation from the entry site [16]. Furthermore, excisional biopsy is therapeutic for atypical mycobacterial lymphadenitis, and may similarly be curative for focal EPTB, as it was for one patient in our series who developed multiple draining sinuses
5. Conclusion
Funding source This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Potential conflicts of interest The authors have no conflicts of interest relevant to this article to disclose. References [1] World Health Organization Global Tuberculosis Report, 2014. Published 2014. Accessed March 1, 2015, http://apps.who.int/iris/bitstream/10665/137094/1/ 9789241564809_eng.pdf. [2] C. Greenaway, A. Sandoe, B. Vissandjee, et al., Tuberculosis: evidence review for newly arriving immigrants and refugees, CMAJ 183 (12) (2011) E939eE951, http://dx.doi.org/10.1503/cmaj.090302. [3] I. Kitai, S.K. Morris, Encounters with an old foe: childhood tuberculosis in Canada, Paediatr. Child. Heal 19 (2) (2014) 89e90. [4] X.T. Ussery, S.E. Valway, M. McKenna, G.M. Cauthen, E. McCray, I.M. Onorato, Epidemiology of tuberculosis among children in the United States: 1985 to 1994, Pediatr. Infect. Dis. J. 15 (8) (1996) 697e704. [5] Angela Houston DCM Extrapulmonary tuberculosis, Med. Baltim. 42 (1) (2014) 18e22. [6] J.M. Fontanilla, A. Barnes, C.F. von Reyn, Current diagnosis and management of peripheral tuberculous lymphadenitis, Clin. Infect. Dis. 53 (6) (2011) 555e562, http://dx.doi.org/10.1093/cid/cir454. [7] A. Kam, L. Ford-Jones, P. Malloy, K. Khan, I. Kitai, Active tuberculosis among adolescents in toronto, Canada: clinical features and delays in diagnosis, Pediatr. Infect. Dis. J. 26 (4) (2007) 355e356, http://dx.doi.org/10.1097/ 01.inf.0000258700.86040.b6. [8] K. Menon, C. Bem, D. Gouldesbrough, D.R. Strachan, A clinical review of 128 cases of head and neck tuberculosis presenting over a 10-year period in Bradford, UK, J. Laryngol. Otol. 121 (4) (2007) 362e368, http://dx.doi.org/ 10.1017/S0022215106002507. [9] K.C. Prasad, S. Sreedharan, Y. Chakravarthy, S.C. Prasad, Tuberculosis in the head and neck: experience in India, J. Laryngol. Otol. 121 (10) (2007) 979e985, http://dx.doi.org/10.1017/S0022215107006913. [10] C.M. Chiesa Estomba, F.A. Betances Reinoso, T. Rivera Schmitz, C.C. Ossa lez Corte s, C. Santidrian Hidalgo, Head and neck tuberEcheverri, M.J. Gonza culosis: 6-year retrospective study, Acta Otorrinolaringol. Esp. (January 2015),
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