Instructive Cases
Endobronchial Lesions Caused by Nontuberculous Mycobacteria in Apparently Healthy Pediatric Patients Carolin Kröner, MD, Matthias Griese, MD, Matthias Kappler, MD, Carola Schoen, MD, Florian Hoffmann, MD, Thomas Nicolai, MD, and Karl Reiter, MD Abstract: Pulmonary disease caused by nontuberculous mycobacteria in healthy children is rare, and its pathogenesis is unknown in most cases and standardized treatment is lacking. Here, we report various endobronchial manifestations in 5 patients including hitherto undescribed diffuse tracheobronchial granulomas in 2 patients. Bronchoscopic debulking was performed in all patients and tuberculostatic treatment in 4. All patients including 1 without tuberculostatic treatment showed remission. Key Words: NTM, intrathoracic infection, pulmonary nontuberculous mycobacteria disease, hilar lymphadenopathia (Pediatr Infect Dis J 2015;34:532–535)
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ontuberculous mycobacteria (NTM) are acid-fast bacilli ubiquitous in the environment. Over 150 species have been described; however, only about 50 species cause human disease.1–5 In otherwise healthy children, the most common manifestation of NTM disease is cervicofacial lymphadenitis.6–8 Rarely, localized organ infections, such as osteomyelitis, mastoiditis and meningitis, have been reported9 as well as isolated skin or soft tissue infections.1 Disseminated disease2,10 appears mainly11 in immunocompromised children. Recently, an increase in the incidence and severity of NTM disease in children has been observed.12,13 NTM pulmonary disease occurs in childhood mainly in cystic fibrosis patients.1,14–19 Nolt et al20 reviewed the literature on pulmonary NTM disease in 43 healthy children between 1930 and 2003: main manifestations were cough, wheezing and/or respiratory distress with (60%) or without (40%) systemic manifestation.20 A few further case reports describe endobronchial lesions and mediastinal or hilar adenopathy caused by NTM20–27 in healthy children as opposed to parenchymal pulmonary disease,28 which appears predominantly in adulthood.27 Neither the diagnostic nor the therapeutic approach has been standardized for pulmonary NTM disease in children nor are the genetic and/or immunological risk factors well established.27,29–31 We here add the description of 5 pediatric patients with endobronchial NTM disease.
Patient 1 A 22-month-old male patient presented with expiratory stridor for 8 weeks and productive cough for 2 weeks. Chest radiography Accepted for publication October 15, 2014. From the Department of Pediatrics, Dr. von Hauner Children’s Hospital, LudwigMaximilians-University, Munich, Germany. The authors have no funding or conflicts of interest to disclose. Address for correspondence: Karl Reiter, MD, Department of Pediatrics, Dr. von Hauner Children’s Hospital, Ludwig-Maximilians-Universitaet Muenchen, Lindwurmstr. 4a, 80337 Munich, Germany. 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 © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0891-3668/15/3405-0532 DOI: 10.1097/INF.0000000000000606
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(CXR) showed opacification of the left upper lobe, and the computerized tomography (CT) scan demonstrated a solid, 2-cm mass in the aortopulmonary window, obstructing the left main bronchus. Bronchoscopy revealed 2 adjoining masses with a subtotal obstruction of the proximal left main stem (see Fig., Supplemental Digital Content 1, http://links.lww.com/INF/C53); in the left upper lobe bronchus, a small area of yellow colored mucosal infiltrate was seen. The masses appeared nodular and had an intact smooth mucosa with areas of yellow-white shimmering appearance. The proximal mass was sheared off without significant bleeding, no caseous material was observed and the bronchial wall appeared intact. Histology revealed a reticulohistiocytic granulomatous, nonnecrotizing inflammation. Mycobacterium avium was grown in culture. Therapy was initiated according to the American Thoracic Society (ATS) guidelines32 with ethambutol, rifampicin and azithromycin. Control bronchoscopies after 6 and 12 months showed regression and after 15 months a complete resolution of the lesions. Therapy was discontinued after 16 months; at 4.5 years follow up, the patient remains asymptomatic, and CXR was normalized.
Patient 2 A 4.6-year-old female patient presented with acute pneumonia, refractory to standard antibiotic treatment. The patient’s uncle suffered from pulmonary sarcoidosis. CXR showed a mediastinal, right perihilar opacity of 2.5 cm. A positron emission tomography/ CT scan was performed because of concern of malignant disease, which demonstrated bilateral hilar lymphadenopathy suspicious of lymphoma. Bronchoscopy showed multiple small inflammatory, mucosal granulomas of the entire tracheobronchial system leading to a cobblestone appearance reminiscent of bronchial sarcoidosis. Biopsy specimens showed an ulcerative chronic bronchitis. Bronchoalveolar lavage (BAL) revealed a nonspecific lymphocytic inflammatory reaction. One perihilar lymph node was removed by thoracotomy. Histology showed an epitheloid cell-like, granulomatous, necrotizing lymphadenitis. Microbial culture grew M. avium. Therapy was initiated with rifampicin, ethambutol and azithromycin, and the patient improved clinically. Control bronchoscopies after 9 and 21 months showed a persistence of the multiple mucosal granulomas in the tracheobronchial system; the bihilar lymphadenopathy also persisted, but the patient was then asymptomatic. M. avium was no longer detectable. No signs of immunodeficiency (Table 1) or sarcoidosis were detected biochemically. Therapy was discontinued after 9 months. At follow-up age of 11.4 years, the patient was asymptomatic.
Patient 3 A 23-month-old female patient presented with 3 weeks of productive cough, wheezing and expiratory stridor. CXR revealed a mass compressing the left main bronchus with hyperinflation of the left lung and mediastinal shift. Chest CT scan demonstrated a subcarinal mass compressing the right pulmonary artery and 2 main bronchi with complete obstruction of the left main bronchus. Bronchoscopy revealed an endobronchial mass in the left main bronchus, which appeared lobulated and slightly yellow-shimmering covered by intact mucosa (see Fig., Supplemental Digital
The Pediatric Infectious Disease Journal • Volume 34, Number 5, May 2015
The Pediatric Infectious Disease Journal • Volume 34, Number 5, May 2015
Endobronchial Lesions
TABLE 1. Immunological Evaluation and Sweat Chloride Patient Age at evaluation (years) White blood cells (×109/L) Neutrophils (%) Lymphocytes (%) IgG (mg/dL) IgA (mg/dL) IgM (mg/dL) Il-12-IFN-γ, p40 after stimulation of full blood with Bacillus Calmette-Guerin Lymphocyte differentiation (cells/μL) Pan-T-lymphocytes/CD3 T-helper cells/CD4 T-suppressor cells/CD8 Activated T-lymphocytes, B-lymphocytes, monocytes/HLADr Activated T-lymphocytes Pan-B-lymphocytes/CD19 NK-cells/CD16 Lymphocyte stimulation with mitogen and antigen* Granulocyte tests (NBT, DHR) Quantitative measurement of adhesion proteins† Tuberculin skin test Acid-fast bacilli in 3 consecutive gastric washings TB-elispot Sweat chloride
1
2
3
4
5
3.3 7 28 64 563 49.8 79.2 Normal
4.9 6.4 36 53 1091 151 84.4 Normal
2 9.2 45 51 ND ND ND Normal
2 10.8 46 45 611 61.4 72.2 Normal
2 11.4 42 45 414 27.4 93.8 ND
3450 1330 1075 1030
2442 1323 984 916
3510 2592 864 1782
3232 2206 923 1898
224 717 224 Normal
339 543 407 Normal
108 270 ND
Normal
205 1488 257
ND ND
Normal ND
ND ND
Normal Normal
Normal ND
Negative Negative
Negative Negative
Negative Negative
Negative ND
Negative ND
Negative ND
Negative ND
ND ND
Negative Normal
ND ND
ND
All values within the age-adapted reference range if not otherwise indicated. *Mitogen contains PHA, OKT-3, CON A, PWM, SAC; antigen contains tetanus, diphtheria, streptolysin O and mumps. †CD11a/a-LFA-1 (Pan-leukocytes), CD11b/C3bi-R (granulocytes, monocytes, NK-cells), CD11c/p150,95 (granulocytes, monocytes) and CD18/b-LFA1 (Pan-leukocytes). NBT indicates nitroblue tetrazolium test; DHR, dihydrorhodamine, oxidative burst; ND, not done.
Content 2, http://links.lww.com/INF/C54) and multiple mucosal granulomas in the trachea and bronchial system (see Fig., Supplemental Digital Content 3, http://links.lww.com/INF/C55). Histologically, an epitheloid cell-like, granulomatous, in part necrotizing inflammation was seen. Neither acid fast bacilli nor NTM were identified by culture. The molecular pathological investigation revealed a polymerase chain reaction (PCR) product typical for Mycobacterium chelonae. Therapy was initiated with ethambutol, rifampicin and clarithromycin. After 3 months, the patient was asymptomatic; however, control bronchoscopy revealed persistence of the endobronchial mass and the endobronchial granulomas. After 12 months, bronchoscopy showed complete resolution of the mass lesion and the granulomas. Therapy was discontinued after 12 months, and the patient remains asymptomatic at 5 years follow up.
Patient 4 A 22-month-old female patient presented with 3 months of productive cough, inspiratory and expiratory stridor, and 12 months of fatigue, night sweats and weight loss. CXR revealed an irregular mediastinum and hyperinflation of the right lung (see Fig., Supplemental Digital Content 4, http://links.lww.com/INF/C56). In the chest CT scan, a 1.6 × 3.5 cm large mass was identified, compressing the ventral trachea and the right main stem bronchus (see Fig., Supplemental Digital Content 5, http://links.lww.com/INF/ C57). Bronchoscopy showed an endobronchial tumor with a subtotal obstruction of the right main stem bronchus (see Fig., Supplemental Digital Content 6, http://links.lww.com/INF/C58). The endobronchial mass had a smooth, yellow-white, nodular appearance without significant vascular injection and appeared compatible with impending lymph node rupture reminiscent of tuberculosis. Endoscopic debulking of the mass was performed, but caseous © 2015 Wolters Kluwer Health, Inc. All rights reserved.
material was not detected. Histologically, a polypous mucosa with squamous cell metaplasia, accelerated epithelial regeneration and a polypous, chronic granulomatous epitheloid cell-like, in part necrotizing inflammation was observed. BAL showed a nonspecific lymphocytosis. M. avium was detected in microbial culture and molecular pathological examination. Treatment with ethambutol, rifampicin and clarithromycin was initiated. One week after the first bronchoscopy, the expiratory stridor recurred and a second endoscopic debulking of the mass was performed. Levofloxacin was added. Three and 6 months after initiation of therapy, the stridor recurred, and bronchoscopies revealed relapses of the mass with nearly complete obstruction of the right main bronchus, requiring repeated endoscopic debulking. M. avium was no longer detectable. Recurrence was suspected to be a reactive inflammatory process, and inhalation therapy with budesonide was initiated; no further relapses occurred. Control bronchoscopy after 12 months showed a nearly complete resolution of the mass. NTM therapy was discontinued after 15 months, budesonide inhalation continued for 2 further months. The patient was symptom-free and had returned to her normal growth percentile. Control bronchoscopy after 27 months showed a complete resolution of the process.
Patient 5 A 2-year-old female patient presented with left-sided wheezing for 10 weeks. CXR showed left hilar lympadenopathy and atelectasis of the left upper lobe, in the CT scan, a 8-mm mass in the left main bronchus was seen. Bronchoscopy showed a smooth, white mass with a complete obstruction of the left upper lobe bronchus (see Fig., Supplemental Digital Content 7, http:// links.lww.com/INF/C59). The mucosa appeared intact without vascular injection; no caseous material was seen at debulking. Histology revealed a necrotizing granulomatous inflammation including www.pidj.com | 533
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Kröner et al
epitheloid cells. Acid fast bacilli were neither detected microscopically nor grown in culture; the molecular pathological investigation revealed PCR products specific for mycobacteria. Mycobacterium tuberculosis and Mycobacterium bovis were ruled out by restriction fragment length polymorphism analysis. The parents declined tuberculostatic treatment of their daughter; control bronchoscopy after 6 weeks showed only a residual lesion in the left upper lobe bronchus, after 3 months only a minimal mucosal infiltrate persisted. The patient remains asymptomatic at 1 year follow up.
MATERIAL AND METHODS Immunological evaluation of the patients included a wide array of laboratory tests including among others neutrophil and lymphocyte function and analysis of the IL-12-IFN-γ-axis (Table 1 for details). Furthermore, a purified protein derivative skin test, 3 repeated gastric washings for acid-fast bacilli stain and a sweat chloride measurement were performed. Informed consent was obtained from the parents or guardians. The study was conducted under the approval of the institutional review board of the University of Munich.
RESULTS All immunological examinations were within the ageadapted reference range for all patients, with the exception of a slight relative lymphocytosis in the differential blood count of patients 1 and 2 (Table 1).
DISCUSSION We here report clinical course, bronchoscopic appearance and treatment of endobronchial NTM infection in 5 pediatric patients. Importantly, we describe a hitherto unknown manifestation of endobronchial NTM disease: 2 of our patients exhibited multiple granulomas in the tracheobronchial system with a cobblestone appearance. In accordance with other reports,20–27,33,34 our 5 patients of age between 1.8 and 4.6 years presented with cough, wheeze and stridor (with or without systemic manifestation), and extensive immunological work-up showed no abnormalities. Bronchoscopically, 4 patients showed broad-based, smooth, well-circumscribed and rounded masses with a white or yellow, shimmering appearance, covered by intact mucosa without significant vascular injection. Some of the lesions were of normal color and some appeared macronodular with a “bag-of-potatoes”-appearance. All lesions were located in large bronchi, and 1 patient had an additional lesion in a segmental bronchus. Other reports describe the endobronchial masses caused by NTM to be fleshy, mucoid, cheesy friable or rubbery gray-white.20,25,27,35,36 Most commonly, the lesions were characterized as granulation tissue, although 1 author25 noted a caseous node. In all our cases, endobronchial masses significantly obstructed a large bronchus; after debulking, an intact bronchial wall was found. Regional lymphadenopathy was discovered in all cases. Caseous material as seen in M. tuberculosis lymph nodes was not found, despite the fact that bronchoscopic findings in 2 of our patients were reminiscent of impending lymph node penetration. In 2 of our patients, a hitherto undescribed bronchoscopic picture in NTM disease was detected: diffuse tracheobronchial granulomata with a cobblestone appearance of the tracheobronchial system. Patient 2 showed only tracheobronchial granulomata. It is unclear, whether the granulomata also contain NTM or they represent reactive inflammatory lesions. Diffuse tracheobronchial granulomata are a well-described pattern in endobronchial sarcoidosis in adult patients,37 however, have not yet been described in NTM pulmonary disease. Microbiological proof of NTM infection, clinical course and laboratory findings inconsistent with sarcoidosis make the diagnosis of sarcoidosis highly unlikely in our
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patients, although, interestingly, 1 of our patients had a positive family history for sarcoidosis. In all our patients, a CT scan of the chest was performed before bronchoscopy, which, however, fell in all cases short of sufficiently characterizing the endobronchial lesions. Symptoms in children with NTM disease may be indistinguishable from foreign body aspiration, and a bronchoscopy may be performed without prior CT scan. From our experience in this limited number of cases, we would suggest that the macroscopic appearance of endobronchial NTM disease in the typical case (as described above) can be sufficiently characteristic to allow a biopsy or debulking procedure without the need to perform a prior CT scan. Differential diagnosis of endobronchial tumors in childhood includes various, almost always histologically benign lesions (e.g., mucoepidermoid and myofibroblast tumors, adenomas, hemangioma). Very rarely a malignant lesion, e.g., mucoepidermoid carcinoma or adenocarcinoma, is encountered. M. avium was detected in 3 patients by microbiological culture of the first bronchial biopsies only. NTM were neither detected microscopically by acid-fast staining nor in the BAL. M. avium is the predominant NTM species causing pulmonary disease in general32,34 and intrathoracic disease in pediatric patients in particular.20,27 In 1 of our patients, PCR products typical for M. chelonae, in one other patient not specifiable mycobacterial PCR products were identified in the molecular pathological investigation only. The full standard ATS criteria for pulmonary NTM disease were thus not fulfilled (i.e., confirmatory identification in a further sample on a second occasion). Clinical course and pathological results, however, made NTM disease in these patients most likely. Moreover, ATS criteria have not been validated in the diagnosis of pediatric pulmonary NTM disease and may be inadequate in this population. Risk factors for acquiring NTM disease discussed in the literature vary from geographical factors (e.g., warmer climates, air-conditioning),38 to genetic factors,39 including non-disease-causing cystic fibrosis transmembrane conductance regulator mutations34; recently, anti-interferon-γ-autoantibodies in patients with disseminated mycobacterial disease have been described.5 Immunological work-up in our patients was negative. although defects in the IL-12-IFN-γaxis have been reported previously.40 Possibly, methods of extended genetic analysis (e.g., whole genome sequencing) have the potential to uncover more subtle immunological defects in these patients. The optimal treatment of pediatric endobronchial NTM disease is still undefined: in 4 of our patients, therapy was performed according to the ATS 2007 guidelines for adult patients.32 Three patients obtained an intermittent dosage scheme 3× per week, which has been proven equally effective.41,42 None or only minor side effects were noted. Macroscopic recurrence of the lesion was seen after start of tuberculostatic treatment in 2 patients, who needed more than one debulking procedure. In 1 of our patients, inhaled steroids possibly inhibited further endobronchial relapses. The diffuse tracheobronchial granulomas and hilar lymphadenopathy persisted in patient 2 up to 21 months after initiation of treatment. On the other hand, patient 5 showed regression of NTM bronchial lesions without any antibiotic treatment after only 1 endoscopic debulking procedure. Alike, in the more prevalent case of childhood NTM disease— cervical adenopathy—surgery is curative, but spontaneous resolution after 12–18 months has also been described.43 Watchful waiting after bronchoscopic debulking may be a valid option in pediatric patients without significant symptoms, and criteria for tuberculostatic treatment have yet to be better defined. REFERENCES 1. Pham-Huy A, Robinson JL, Tapiéro B, et al. Current trends in nontuberculous mycobacteria infections in Canadian children: a pediatric investigators collaborative network on infections in Canada (PICNIC) study. Paediatr Child Health. 2010;15:276–282.
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2. Hoyt L, Oleske J, Holland B, et al. Nontuberculous mycobacteria in children with acquired immunodeficiency syndrome. Pediatr Infect Dis J. 1992;11:354–360. 3. Gupta SK, Katz BZ. Intrathoracic disease associated with Mycobacterium avium-intracellulare complex in otherwise healthy children: diagnostic and therapeutic considerations. Pediatrics. 1994;94:741–742. 4. Saleeb P, Olivier KN. Pulmonary nontuberculous mycobacterial disease: new insights into risk factors for susceptibility, epidemiology, and approaches to management in immunocompetent and immunocompromised patients. Curr Infect Dis Rep. 2010;12:198–203. 5. O’Connell E, Rosen L, LaRue R, et al. The first US domestic report of disseminated Mycobacterium avium complex and anti-interferon-γ autoantibodies. J Clin Immunol. 2014:34:928–932. 6. Knuf M, Habermehl P, Zepp F, et al. [Lymphadenitis colli due to non-tuberculous mycobacteria (NTM): a case-series and review of the literature]. Klin Padiatr. 2003;215:9–15. 7. Lindeboom JA. Surgical treatment for nontuberculous mycobacterial (NTM) cervicofacial lymphadenitis in children. J Oral Maxillofac Surg. 2012;70:345–348. 8. Pilkington EF, MacArthur CJ, Beekmann SE, et al. Treatment patterns of pediatric nontuberculous mycobacterial (NTM) cervical lymphadenitis as reported by nationwide surveys of pediatric otolaryngology and infectious disease societies. Int J Pediatr Otorhinolaryngol. 2010;74:343–346. 9. Stone AB, Schelonka RL, Drehner DM, et al. Disseminated Mycobacterium avium complex in non-human immunodeficiency virus-infected pediatric patients. Pediatr Infect Dis J. 1992;11:960–964. 10. Wei MC, Banaei N, Yakrus MA, et al. Nontuberculous mycobacteria infections in immunocompromised patients: single institution experience. J Pediatr Hematol Oncol. 2009;31:556–560. 11. Montague NS, Garola RE, González I, et al. Disseminated nontuberculous mycobacterial infection in two children with different immune responses. Pediatr Dev Pathol. 2013;16:372–377. 12. Marras TK, Chedore P, Ying AM, et al. Isolation prevalence of pulmonary non-tuberculous mycobacteria in Ontario, 1997 2003. Thorax. 2007;62:661–666. 13. Vu TT, Daniel SJ, Quach C. Nontuberculous mycobacteria in children: a changing pattern. J Otolaryngol. 2005;34(suppl 1):S40–S44. 14. Oliver A, Maiz L, Cantón R, et al. Nontuberculous mycobacteria in patients with cystic fibrosis. Clin Infect Dis. 2001;32:1298–1303. 15. Olivier KN; NTM in CF Study Group. The natural history of nontuberculous mycobacteria in patients with cystic fibrosis. Paediatr Respir Rev. 2004;5(suppl A):S213–S216. 16. Olivier KN, Weber DJ, Lee JH, et al; Nontuberculous Mycobacteria in Cystic Fibrosis Study Group. Nontuberculous mycobacteria. II: nestedcohort study of impact on cystic fibrosis lung disease. Am J Respir Crit Care Med. 2003;167:835–840. 17. Steinkamp G, Wiedemann B, Rietschel E, et al; Emerging Bacteria Study Group. Prospective evaluation of emerging bacteria in cystic fibrosis. J Cyst Fibros. 2005;4:41–48. 18. Do PC, Nussbaum E, Moua J, et al. Clinical significance of respiratory isolates for Mycobacterium abscessus complex from pediatric patients. Pediatr Pulmonol. 2013;48:470–480. 19. Kröner C, Kappler M, Grimmelt A, et al. Molecular epidemiology of nontuberculous mycobacteria in a German CF Center and Clinical Course of NTM Positive Patients. Open J Med Microbiol. 2013;3:39–47 20. Nolt D, Michaels MG, Wald ER. Intrathoracic disease from nontuberculous mycobacteria in children: two cases and a review of the literature. Pediatrics. 2003;112:e434. 21. Fergie JE, Milligan TW, Henderson BM, et al. Intrathoracic Mycobacterium avium complex infection in immunocompetent children: case report and review. Clin Infect Dis. 1997;24:250–253. 22. Levelink B, de Vries E, van Dissel JT, et al. Pulmonary Mycobacterium avium intracellulare infection in an immunocompetent child. Pediatr Infect Dis J. 2004;23:892.
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23. Osorio A, Kessler RM, Guruprasad H, et al. Isolated intrathoracic presentation of Mycobacterium avium complex in an immunocompetent child. Pediatr Radiol. 2001;31:848–851. 24. Litman DA, Shah UK, Pawel BR. Isolated endobronchial atypical mycobacterium in a child: a case report and review of the literature. Int J Pediatr Otorhinolaryngol. 2000;55:65–68. 25. Dore ND, LeSouëf PN, Masters B, et al. Atypical mycobacterial pulmonary disease and bronchial obstruction in HIV-negative children. Pediatr Pulmonol. 1998;26:380–388. 26. Piedimonte G, Wolford ET, Fordham LA, et al. Mediastinal lymphadenopathy caused by Mycobacterium avium-intracellulare complex in a child with normal immunity: successful treatment with anti-mycobacterial drugs and laser bronchoscopy. Pediatr Pulmonol. 1997;24:287–291. 27. Freeman AF, Olivier KN, Rubio TT, et al. Intrathoracic nontuberculous mycobacterial infections in otherwise healthy children. Pediatr Pulmonol. 2009;44:1051–1056. 28. Glatstein M, Scolnik D, Bensira L, et al. Lung abscess due to non-tuberculous, non-Mycobacterium fortuitum in a neonate. Pediatr Pulmonol. 2012;47:1034–1037. 29. Vankayalapati R, Wizel B, Samten B, et al. Cytokine profiles in immunocompetent persons infected with Mycobacterium avium complex. J Infect Dis. 2001;183:478–484. 30. Safdar A, White DA, Stover D, et al. Profound interferon gamma deficiency in patients with chronic pulmonary nontuberculous mycobacteriosis. Am J Med. 2002;113:756–759. 31. Colombo RE, Hill SC, Claypool RJ, et al. Familial clustering of pulmonary nontuberculous mycobacterial disease. Chest. 2010;137:629–634. 32. Griffith DE, Aksamit T, Brown-Elliott BA, et al; ATS Mycobacterial Diseases Subcommittee; American Thoracic Society; Infectious Disease Society of America. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med. 2007;175:367–416. 33. Serour F, Mizrahi A, Somekh E, et al. Analysis of the interleukin-12/interferon-gamma pathway in children with non-tuberculous mycobacterial cervical lymphadenitis. Eur J Pediatr. 2007;166:835–841. 34. Saleeb P, Olivier KN. Pulmonary nontuberculous mycobacterial dis ease: new insights into risk factors for susceptibility, epidemiology, and approaches to management in immunocompetent and immunocompromised patients. Curr Infect Dis Rep. 2010;12:198–203. 35. del Rio Camacho G, Soriano Guillén L, Flandes Aldeyturriaga J, et al. Endobronchial atypical mycobacteria in an immunocompetent child. Pediatr Pulmonol. 2010;45:511–513. 36. Kelsey DS, Chambers RT, Hudspeth AS. Nontuberculous mycobacterial infection presenting as a mediastinal mass. J Pediatr. 1981;98:431–432. 37. Polychronopoulos VS, Prakash UB. Airway involvement in sarcoidosis. Chest. 2009;136:1371–1380. 38. Colin A, Basora E, Yousef S. Mycobacterium avium complex (MAC) presenting as the first infection in a child with cystic fibrosis. Pediatr Pulmonol. [published online ahead of print September 8, 2014]. doi: 10.1002/ppul.23101. 39. Haverkamp MH, van de Vosse E, van Dissel JT. Nontuberculous mycobacterial infections in children with inborn errors of the immune system. J Infect. 2014;68(suppl 1):S134–S150. 40. Newport MJ, Huxley CM, Huston S, et al. A mutation in the interferongamma-receptor gene and susceptibility to mycobacterial infection. N Engl J Med. 1996;335:1941–1949. 41. Griffith DE, Brown BA, Girard WM, et al. Azithromycin-containing regimens for treatment of Mycobacterium avium complex lung disease. Clin Infect Dis. 2001;32:1547–1553. 42. Griffith DE, Brown BA, Cegielski P, et al. Early results (at 6 months) with intermittent clarithromycin-including regimens for lung disease due to Mycobacterium avium complex. Clin Infect Dis. 2000;30:288–292. 43. Mandell DL, Wald ER, Michaels MG, et al. Management of nontuberculous mycobacterial cervical lymphadenitis. Arch Otolaryngol Head Neck Surg. 2003;129:341–344.
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Endobronchial Lesions Caused by Nontuberculous Mycobacteria in Apparently Healthy Pediatric Patients Carolin Kröner, MD, Matthias Griese, MD, Matthias Kappler, MD, Carola Schoen, MD, Florian Hoffmann, MD, Thomas Nicolai, MD, and Karl Reiter, MD Abstract: Pulmonary disease caused by nontuberculous mycobacteria in healthy children is rare, and its pathogenesis is unknown in most cases and standardized treatment is lacking. Here, we report various endobronchial manifestations in 5 patients including hitherto undescribed diffuse tracheobronchial granulomas in 2 patients. Bronchoscopic debulking was performed in all patients and tuberculostatic treatment in 4. All patients including 1 without tuberculostatic treatment showed remission. Key Words: NTM, intrathoracic infection, pulmonary nontuberculous mycobacteria disease, hilar lymphadenopathia (Pediatr Infect Dis J 2015;34:532–535)
N
ontuberculous mycobacteria (NTM) are acid-fast bacilli ubiquitous in the environment. Over 150 species have been described; however, only about 50 species cause human disease.1–5 In otherwise healthy children, the most common manifestation of NTM disease is cervicofacial lymphadenitis.6–8 Rarely, localized organ infections, such as osteomyelitis, mastoiditis and meningitis, have been reported9 as well as isolated skin or soft tissue infections.1 Disseminated disease2,10 appears mainly11 in immunocompromised children. Recently, an increase in the incidence and severity of NTM disease in children has been observed.12,13 NTM pulmonary disease occurs in childhood mainly in cystic fibrosis patients.1,14–19 Nolt et al20 reviewed the literature on pulmonary NTM disease in 43 healthy children between 1930 and 2003: main manifestations were cough, wheezing and/or respiratory distress with (60%) or without (40%) systemic manifestation.20 A few further case reports describe endobronchial lesions and mediastinal or hilar adenopathy caused by NTM20–27 in healthy children as opposed to parenchymal pulmonary disease,28 which appears predominantly in adulthood.27 Neither the diagnostic nor the therapeutic approach has been standardized for pulmonary NTM disease in children nor are the genetic and/or immunological risk factors well established.27,29–31 We here add the description of 5 pediatric patients with endobronchial NTM disease.
Patient 1 A 22-month-old male patient presented with expiratory stridor for 8 weeks and productive cough for 2 weeks. Chest radiography Accepted for publication October 15, 2014. From the Department of Pediatrics, Dr. von Hauner Children’s Hospital, LudwigMaximilians-University, Munich, Germany. The authors have no funding or conflicts of interest to disclose. Address for correspondence: Karl Reiter, MD, Department of Pediatrics, Dr. von Hauner Children’s Hospital, Ludwig-Maximilians-Universitaet Muenchen, Lindwurmstr. 4a, 80337 Munich, Germany. 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 © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0891-3668/15/3405-0532 DOI: 10.1097/INF.0000000000000606
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(CXR) showed opacification of the left upper lobe, and the computerized tomography (CT) scan demonstrated a solid, 2-cm mass in the aortopulmonary window, obstructing the left main bronchus. Bronchoscopy revealed 2 adjoining masses with a subtotal obstruction of the proximal left main stem (see Fig., Supplemental Digital Content 1, http://links.lww.com/INF/C53); in the left upper lobe bronchus, a small area of yellow colored mucosal infiltrate was seen. The masses appeared nodular and had an intact smooth mucosa with areas of yellow-white shimmering appearance. The proximal mass was sheared off without significant bleeding, no caseous material was observed and the bronchial wall appeared intact. Histology revealed a reticulohistiocytic granulomatous, nonnecrotizing inflammation. Mycobacterium avium was grown in culture. Therapy was initiated according to the American Thoracic Society (ATS) guidelines32 with ethambutol, rifampicin and azithromycin. Control bronchoscopies after 6 and 12 months showed regression and after 15 months a complete resolution of the lesions. Therapy was discontinued after 16 months; at 4.5 years follow up, the patient remains asymptomatic, and CXR was normalized.
Patient 2 A 4.6-year-old female patient presented with acute pneumonia, refractory to standard antibiotic treatment. The patient’s uncle suffered from pulmonary sarcoidosis. CXR showed a mediastinal, right perihilar opacity of 2.5 cm. A positron emission tomography/ CT scan was performed because of concern of malignant disease, which demonstrated bilateral hilar lymphadenopathy suspicious of lymphoma. Bronchoscopy showed multiple small inflammatory, mucosal granulomas of the entire tracheobronchial system leading to a cobblestone appearance reminiscent of bronchial sarcoidosis. Biopsy specimens showed an ulcerative chronic bronchitis. Bronchoalveolar lavage (BAL) revealed a nonspecific lymphocytic inflammatory reaction. One perihilar lymph node was removed by thoracotomy. Histology showed an epitheloid cell-like, granulomatous, necrotizing lymphadenitis. Microbial culture grew M. avium. Therapy was initiated with rifampicin, ethambutol and azithromycin, and the patient improved clinically. Control bronchoscopies after 9 and 21 months showed a persistence of the multiple mucosal granulomas in the tracheobronchial system; the bihilar lymphadenopathy also persisted, but the patient was then asymptomatic. M. avium was no longer detectable. No signs of immunodeficiency (Table 1) or sarcoidosis were detected biochemically. Therapy was discontinued after 9 months. At follow-up age of 11.4 years, the patient was asymptomatic.
Patient 3 A 23-month-old female patient presented with 3 weeks of productive cough, wheezing and expiratory stridor. CXR revealed a mass compressing the left main bronchus with hyperinflation of the left lung and mediastinal shift. Chest CT scan demonstrated a subcarinal mass compressing the right pulmonary artery and 2 main bronchi with complete obstruction of the left main bronchus. Bronchoscopy revealed an endobronchial mass in the left main bronchus, which appeared lobulated and slightly yellow-shimmering covered by intact mucosa (see Fig., Supplemental Digital
The Pediatric Infectious Disease Journal • Volume 34, Number 5, May 2015
The Pediatric Infectious Disease Journal • Volume 34, Number 5, May 2015
Endobronchial Lesions
TABLE 1. Immunological Evaluation and Sweat Chloride Patient Age at evaluation (years) White blood cells (×109/L) Neutrophils (%) Lymphocytes (%) IgG (mg/dL) IgA (mg/dL) IgM (mg/dL) Il-12-IFN-γ, p40 after stimulation of full blood with Bacillus Calmette-Guerin Lymphocyte differentiation (cells/μL) Pan-T-lymphocytes/CD3 T-helper cells/CD4 T-suppressor cells/CD8 Activated T-lymphocytes, B-lymphocytes, monocytes/HLADr Activated T-lymphocytes Pan-B-lymphocytes/CD19 NK-cells/CD16 Lymphocyte stimulation with mitogen and antigen* Granulocyte tests (NBT, DHR) Quantitative measurement of adhesion proteins† Tuberculin skin test Acid-fast bacilli in 3 consecutive gastric washings TB-elispot Sweat chloride
1
2
3
4
5
3.3 7 28 64 563 49.8 79.2 Normal
4.9 6.4 36 53 1091 151 84.4 Normal
2 9.2 45 51 ND ND ND Normal
2 10.8 46 45 611 61.4 72.2 Normal
2 11.4 42 45 414 27.4 93.8 ND
3450 1330 1075 1030
2442 1323 984 916
3510 2592 864 1782
3232 2206 923 1898
224 717 224 Normal
339 543 407 Normal
108 270 ND
Normal
205 1488 257
ND ND
Normal ND
ND ND
Normal Normal
Normal ND
Negative Negative
Negative Negative
Negative Negative
Negative ND
Negative ND
Negative ND
Negative ND
ND ND
Negative Normal
ND ND
ND
All values within the age-adapted reference range if not otherwise indicated. *Mitogen contains PHA, OKT-3, CON A, PWM, SAC; antigen contains tetanus, diphtheria, streptolysin O and mumps. †CD11a/a-LFA-1 (Pan-leukocytes), CD11b/C3bi-R (granulocytes, monocytes, NK-cells), CD11c/p150,95 (granulocytes, monocytes) and CD18/b-LFA1 (Pan-leukocytes). NBT indicates nitroblue tetrazolium test; DHR, dihydrorhodamine, oxidative burst; ND, not done.
Content 2, http://links.lww.com/INF/C54) and multiple mucosal granulomas in the trachea and bronchial system (see Fig., Supplemental Digital Content 3, http://links.lww.com/INF/C55). Histologically, an epitheloid cell-like, granulomatous, in part necrotizing inflammation was seen. Neither acid fast bacilli nor NTM were identified by culture. The molecular pathological investigation revealed a polymerase chain reaction (PCR) product typical for Mycobacterium chelonae. Therapy was initiated with ethambutol, rifampicin and clarithromycin. After 3 months, the patient was asymptomatic; however, control bronchoscopy revealed persistence of the endobronchial mass and the endobronchial granulomas. After 12 months, bronchoscopy showed complete resolution of the mass lesion and the granulomas. Therapy was discontinued after 12 months, and the patient remains asymptomatic at 5 years follow up.
Patient 4 A 22-month-old female patient presented with 3 months of productive cough, inspiratory and expiratory stridor, and 12 months of fatigue, night sweats and weight loss. CXR revealed an irregular mediastinum and hyperinflation of the right lung (see Fig., Supplemental Digital Content 4, http://links.lww.com/INF/C56). In the chest CT scan, a 1.6 × 3.5 cm large mass was identified, compressing the ventral trachea and the right main stem bronchus (see Fig., Supplemental Digital Content 5, http://links.lww.com/INF/ C57). Bronchoscopy showed an endobronchial tumor with a subtotal obstruction of the right main stem bronchus (see Fig., Supplemental Digital Content 6, http://links.lww.com/INF/C58). The endobronchial mass had a smooth, yellow-white, nodular appearance without significant vascular injection and appeared compatible with impending lymph node rupture reminiscent of tuberculosis. Endoscopic debulking of the mass was performed, but caseous © 2015 Wolters Kluwer Health, Inc. All rights reserved.
material was not detected. Histologically, a polypous mucosa with squamous cell metaplasia, accelerated epithelial regeneration and a polypous, chronic granulomatous epitheloid cell-like, in part necrotizing inflammation was observed. BAL showed a nonspecific lymphocytosis. M. avium was detected in microbial culture and molecular pathological examination. Treatment with ethambutol, rifampicin and clarithromycin was initiated. One week after the first bronchoscopy, the expiratory stridor recurred and a second endoscopic debulking of the mass was performed. Levofloxacin was added. Three and 6 months after initiation of therapy, the stridor recurred, and bronchoscopies revealed relapses of the mass with nearly complete obstruction of the right main bronchus, requiring repeated endoscopic debulking. M. avium was no longer detectable. Recurrence was suspected to be a reactive inflammatory process, and inhalation therapy with budesonide was initiated; no further relapses occurred. Control bronchoscopy after 12 months showed a nearly complete resolution of the mass. NTM therapy was discontinued after 15 months, budesonide inhalation continued for 2 further months. The patient was symptom-free and had returned to her normal growth percentile. Control bronchoscopy after 27 months showed a complete resolution of the process.
Patient 5 A 2-year-old female patient presented with left-sided wheezing for 10 weeks. CXR showed left hilar lympadenopathy and atelectasis of the left upper lobe, in the CT scan, a 8-mm mass in the left main bronchus was seen. Bronchoscopy showed a smooth, white mass with a complete obstruction of the left upper lobe bronchus (see Fig., Supplemental Digital Content 7, http:// links.lww.com/INF/C59). The mucosa appeared intact without vascular injection; no caseous material was seen at debulking. Histology revealed a necrotizing granulomatous inflammation including www.pidj.com | 533
The Pediatric Infectious Disease Journal • Volume 34, Number 5, May 2015
Kröner et al
epitheloid cells. Acid fast bacilli were neither detected microscopically nor grown in culture; the molecular pathological investigation revealed PCR products specific for mycobacteria. Mycobacterium tuberculosis and Mycobacterium bovis were ruled out by restriction fragment length polymorphism analysis. The parents declined tuberculostatic treatment of their daughter; control bronchoscopy after 6 weeks showed only a residual lesion in the left upper lobe bronchus, after 3 months only a minimal mucosal infiltrate persisted. The patient remains asymptomatic at 1 year follow up.
MATERIAL AND METHODS Immunological evaluation of the patients included a wide array of laboratory tests including among others neutrophil and lymphocyte function and analysis of the IL-12-IFN-γ-axis (Table 1 for details). Furthermore, a purified protein derivative skin test, 3 repeated gastric washings for acid-fast bacilli stain and a sweat chloride measurement were performed. Informed consent was obtained from the parents or guardians. The study was conducted under the approval of the institutional review board of the University of Munich.
RESULTS All immunological examinations were within the ageadapted reference range for all patients, with the exception of a slight relative lymphocytosis in the differential blood count of patients 1 and 2 (Table 1).
DISCUSSION We here report clinical course, bronchoscopic appearance and treatment of endobronchial NTM infection in 5 pediatric patients. Importantly, we describe a hitherto unknown manifestation of endobronchial NTM disease: 2 of our patients exhibited multiple granulomas in the tracheobronchial system with a cobblestone appearance. In accordance with other reports,20–27,33,34 our 5 patients of age between 1.8 and 4.6 years presented with cough, wheeze and stridor (with or without systemic manifestation), and extensive immunological work-up showed no abnormalities. Bronchoscopically, 4 patients showed broad-based, smooth, well-circumscribed and rounded masses with a white or yellow, shimmering appearance, covered by intact mucosa without significant vascular injection. Some of the lesions were of normal color and some appeared macronodular with a “bag-of-potatoes”-appearance. All lesions were located in large bronchi, and 1 patient had an additional lesion in a segmental bronchus. Other reports describe the endobronchial masses caused by NTM to be fleshy, mucoid, cheesy friable or rubbery gray-white.20,25,27,35,36 Most commonly, the lesions were characterized as granulation tissue, although 1 author25 noted a caseous node. In all our cases, endobronchial masses significantly obstructed a large bronchus; after debulking, an intact bronchial wall was found. Regional lymphadenopathy was discovered in all cases. Caseous material as seen in M. tuberculosis lymph nodes was not found, despite the fact that bronchoscopic findings in 2 of our patients were reminiscent of impending lymph node penetration. In 2 of our patients, a hitherto undescribed bronchoscopic picture in NTM disease was detected: diffuse tracheobronchial granulomata with a cobblestone appearance of the tracheobronchial system. Patient 2 showed only tracheobronchial granulomata. It is unclear, whether the granulomata also contain NTM or they represent reactive inflammatory lesions. Diffuse tracheobronchial granulomata are a well-described pattern in endobronchial sarcoidosis in adult patients,37 however, have not yet been described in NTM pulmonary disease. Microbiological proof of NTM infection, clinical course and laboratory findings inconsistent with sarcoidosis make the diagnosis of sarcoidosis highly unlikely in our
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patients, although, interestingly, 1 of our patients had a positive family history for sarcoidosis. In all our patients, a CT scan of the chest was performed before bronchoscopy, which, however, fell in all cases short of sufficiently characterizing the endobronchial lesions. Symptoms in children with NTM disease may be indistinguishable from foreign body aspiration, and a bronchoscopy may be performed without prior CT scan. From our experience in this limited number of cases, we would suggest that the macroscopic appearance of endobronchial NTM disease in the typical case (as described above) can be sufficiently characteristic to allow a biopsy or debulking procedure without the need to perform a prior CT scan. Differential diagnosis of endobronchial tumors in childhood includes various, almost always histologically benign lesions (e.g., mucoepidermoid and myofibroblast tumors, adenomas, hemangioma). Very rarely a malignant lesion, e.g., mucoepidermoid carcinoma or adenocarcinoma, is encountered. M. avium was detected in 3 patients by microbiological culture of the first bronchial biopsies only. NTM were neither detected microscopically by acid-fast staining nor in the BAL. M. avium is the predominant NTM species causing pulmonary disease in general32,34 and intrathoracic disease in pediatric patients in particular.20,27 In 1 of our patients, PCR products typical for M. chelonae, in one other patient not specifiable mycobacterial PCR products were identified in the molecular pathological investigation only. The full standard ATS criteria for pulmonary NTM disease were thus not fulfilled (i.e., confirmatory identification in a further sample on a second occasion). Clinical course and pathological results, however, made NTM disease in these patients most likely. Moreover, ATS criteria have not been validated in the diagnosis of pediatric pulmonary NTM disease and may be inadequate in this population. Risk factors for acquiring NTM disease discussed in the literature vary from geographical factors (e.g., warmer climates, air-conditioning),38 to genetic factors,39 including non-disease-causing cystic fibrosis transmembrane conductance regulator mutations34; recently, anti-interferon-γ-autoantibodies in patients with disseminated mycobacterial disease have been described.5 Immunological work-up in our patients was negative. although defects in the IL-12-IFN-γaxis have been reported previously.40 Possibly, methods of extended genetic analysis (e.g., whole genome sequencing) have the potential to uncover more subtle immunological defects in these patients. The optimal treatment of pediatric endobronchial NTM disease is still undefined: in 4 of our patients, therapy was performed according to the ATS 2007 guidelines for adult patients.32 Three patients obtained an intermittent dosage scheme 3× per week, which has been proven equally effective.41,42 None or only minor side effects were noted. Macroscopic recurrence of the lesion was seen after start of tuberculostatic treatment in 2 patients, who needed more than one debulking procedure. In 1 of our patients, inhaled steroids possibly inhibited further endobronchial relapses. The diffuse tracheobronchial granulomas and hilar lymphadenopathy persisted in patient 2 up to 21 months after initiation of treatment. On the other hand, patient 5 showed regression of NTM bronchial lesions without any antibiotic treatment after only 1 endoscopic debulking procedure. Alike, in the more prevalent case of childhood NTM disease— cervical adenopathy—surgery is curative, but spontaneous resolution after 12–18 months has also been described.43 Watchful waiting after bronchoscopic debulking may be a valid option in pediatric patients without significant symptoms, and criteria for tuberculostatic treatment have yet to be better defined. REFERENCES 1. Pham-Huy A, Robinson JL, Tapiéro B, et al. Current trends in nontuberculous mycobacteria infections in Canadian children: a pediatric investigators collaborative network on infections in Canada (PICNIC) study. Paediatr Child Health. 2010;15:276–282.
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2. Hoyt L, Oleske J, Holland B, et al. Nontuberculous mycobacteria in children with acquired immunodeficiency syndrome. Pediatr Infect Dis J. 1992;11:354–360. 3. Gupta SK, Katz BZ. Intrathoracic disease associated with Mycobacterium avium-intracellulare complex in otherwise healthy children: diagnostic and therapeutic considerations. Pediatrics. 1994;94:741–742. 4. Saleeb P, Olivier KN. Pulmonary nontuberculous mycobacterial disease: new insights into risk factors for susceptibility, epidemiology, and approaches to management in immunocompetent and immunocompromised patients. Curr Infect Dis Rep. 2010;12:198–203. 5. O’Connell E, Rosen L, LaRue R, et al. The first US domestic report of disseminated Mycobacterium avium complex and anti-interferon-γ autoantibodies. J Clin Immunol. 2014:34:928–932. 6. Knuf M, Habermehl P, Zepp F, et al. [Lymphadenitis colli due to non-tuberculous mycobacteria (NTM): a case-series and review of the literature]. Klin Padiatr. 2003;215:9–15. 7. Lindeboom JA. Surgical treatment for nontuberculous mycobacterial (NTM) cervicofacial lymphadenitis in children. J Oral Maxillofac Surg. 2012;70:345–348. 8. Pilkington EF, MacArthur CJ, Beekmann SE, et al. Treatment patterns of pediatric nontuberculous mycobacterial (NTM) cervical lymphadenitis as reported by nationwide surveys of pediatric otolaryngology and infectious disease societies. Int J Pediatr Otorhinolaryngol. 2010;74:343–346. 9. Stone AB, Schelonka RL, Drehner DM, et al. Disseminated Mycobacterium avium complex in non-human immunodeficiency virus-infected pediatric patients. Pediatr Infect Dis J. 1992;11:960–964. 10. Wei MC, Banaei N, Yakrus MA, et al. Nontuberculous mycobacteria infections in immunocompromised patients: single institution experience. J Pediatr Hematol Oncol. 2009;31:556–560. 11. Montague NS, Garola RE, González I, et al. Disseminated nontuberculous mycobacterial infection in two children with different immune responses. Pediatr Dev Pathol. 2013;16:372–377. 12. Marras TK, Chedore P, Ying AM, et al. Isolation prevalence of pulmonary non-tuberculous mycobacteria in Ontario, 1997 2003. Thorax. 2007;62:661–666. 13. Vu TT, Daniel SJ, Quach C. Nontuberculous mycobacteria in children: a changing pattern. J Otolaryngol. 2005;34(suppl 1):S40–S44. 14. Oliver A, Maiz L, Cantón R, et al. Nontuberculous mycobacteria in patients with cystic fibrosis. Clin Infect Dis. 2001;32:1298–1303. 15. Olivier KN; NTM in CF Study Group. The natural history of nontuberculous mycobacteria in patients with cystic fibrosis. Paediatr Respir Rev. 2004;5(suppl A):S213–S216. 16. Olivier KN, Weber DJ, Lee JH, et al; Nontuberculous Mycobacteria in Cystic Fibrosis Study Group. Nontuberculous mycobacteria. II: nestedcohort study of impact on cystic fibrosis lung disease. Am J Respir Crit Care Med. 2003;167:835–840. 17. Steinkamp G, Wiedemann B, Rietschel E, et al; Emerging Bacteria Study Group. Prospective evaluation of emerging bacteria in cystic fibrosis. J Cyst Fibros. 2005;4:41–48. 18. Do PC, Nussbaum E, Moua J, et al. Clinical significance of respiratory isolates for Mycobacterium abscessus complex from pediatric patients. Pediatr Pulmonol. 2013;48:470–480. 19. Kröner C, Kappler M, Grimmelt A, et al. Molecular epidemiology of nontuberculous mycobacteria in a German CF Center and Clinical Course of NTM Positive Patients. Open J Med Microbiol. 2013;3:39–47 20. Nolt D, Michaels MG, Wald ER. Intrathoracic disease from nontuberculous mycobacteria in children: two cases and a review of the literature. Pediatrics. 2003;112:e434. 21. Fergie JE, Milligan TW, Henderson BM, et al. Intrathoracic Mycobacterium avium complex infection in immunocompetent children: case report and review. Clin Infect Dis. 1997;24:250–253. 22. Levelink B, de Vries E, van Dissel JT, et al. Pulmonary Mycobacterium avium intracellulare infection in an immunocompetent child. Pediatr Infect Dis J. 2004;23:892.
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23. Osorio A, Kessler RM, Guruprasad H, et al. Isolated intrathoracic presentation of Mycobacterium avium complex in an immunocompetent child. Pediatr Radiol. 2001;31:848–851. 24. Litman DA, Shah UK, Pawel BR. Isolated endobronchial atypical mycobacterium in a child: a case report and review of the literature. Int J Pediatr Otorhinolaryngol. 2000;55:65–68. 25. Dore ND, LeSouëf PN, Masters B, et al. Atypical mycobacterial pulmonary disease and bronchial obstruction in HIV-negative children. Pediatr Pulmonol. 1998;26:380–388. 26. Piedimonte G, Wolford ET, Fordham LA, et al. Mediastinal lymphadenopathy caused by Mycobacterium avium-intracellulare complex in a child with normal immunity: successful treatment with anti-mycobacterial drugs and laser bronchoscopy. Pediatr Pulmonol. 1997;24:287–291. 27. Freeman AF, Olivier KN, Rubio TT, et al. Intrathoracic nontuberculous mycobacterial infections in otherwise healthy children. Pediatr Pulmonol. 2009;44:1051–1056. 28. Glatstein M, Scolnik D, Bensira L, et al. Lung abscess due to non-tuberculous, non-Mycobacterium fortuitum in a neonate. Pediatr Pulmonol. 2012;47:1034–1037. 29. Vankayalapati R, Wizel B, Samten B, et al. Cytokine profiles in immunocompetent persons infected with Mycobacterium avium complex. J Infect Dis. 2001;183:478–484. 30. Safdar A, White DA, Stover D, et al. Profound interferon gamma deficiency in patients with chronic pulmonary nontuberculous mycobacteriosis. Am J Med. 2002;113:756–759. 31. Colombo RE, Hill SC, Claypool RJ, et al. Familial clustering of pulmonary nontuberculous mycobacterial disease. Chest. 2010;137:629–634. 32. Griffith DE, Aksamit T, Brown-Elliott BA, et al; ATS Mycobacterial Diseases Subcommittee; American Thoracic Society; Infectious Disease Society of America. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med. 2007;175:367–416. 33. Serour F, Mizrahi A, Somekh E, et al. Analysis of the interleukin-12/interferon-gamma pathway in children with non-tuberculous mycobacterial cervical lymphadenitis. Eur J Pediatr. 2007;166:835–841. 34. Saleeb P, Olivier KN. Pulmonary nontuberculous mycobacterial dis ease: new insights into risk factors for susceptibility, epidemiology, and approaches to management in immunocompetent and immunocompromised patients. Curr Infect Dis Rep. 2010;12:198–203. 35. del Rio Camacho G, Soriano Guillén L, Flandes Aldeyturriaga J, et al. Endobronchial atypical mycobacteria in an immunocompetent child. Pediatr Pulmonol. 2010;45:511–513. 36. Kelsey DS, Chambers RT, Hudspeth AS. Nontuberculous mycobacterial infection presenting as a mediastinal mass. J Pediatr. 1981;98:431–432. 37. Polychronopoulos VS, Prakash UB. Airway involvement in sarcoidosis. Chest. 2009;136:1371–1380. 38. Colin A, Basora E, Yousef S. Mycobacterium avium complex (MAC) presenting as the first infection in a child with cystic fibrosis. Pediatr Pulmonol. [published online ahead of print September 8, 2014]. doi: 10.1002/ppul.23101. 39. Haverkamp MH, van de Vosse E, van Dissel JT. Nontuberculous mycobacterial infections in children with inborn errors of the immune system. J Infect. 2014;68(suppl 1):S134–S150. 40. Newport MJ, Huxley CM, Huston S, et al. A mutation in the interferongamma-receptor gene and susceptibility to mycobacterial infection. N Engl J Med. 1996;335:1941–1949. 41. Griffith DE, Brown BA, Girard WM, et al. Azithromycin-containing regimens for treatment of Mycobacterium avium complex lung disease. Clin Infect Dis. 2001;32:1547–1553. 42. Griffith DE, Brown BA, Cegielski P, et al. Early results (at 6 months) with intermittent clarithromycin-including regimens for lung disease due to Mycobacterium avium complex. Clin Infect Dis. 2000;30:288–292. 43. Mandell DL, Wald ER, Michaels MG, et al. Management of nontuberculous mycobacterial cervical lymphadenitis. Arch Otolaryngol Head Neck Surg. 2003;129:341–344.
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