Mediastinal Nontuberculous Mycobacterial Infection in Children: A Multidisciplinary Approach

Background: Mediastinal infections due to nontuberculous mycobacteria remain an exceedingly rare entity. Most cases in the published literature do not include pediatric patients. Due to their clinical infrequency, poor response to antimicrobial therapy and often precarious anatomical location, the optimal management of these lesions can be challenging. Methods: Retrospective medical record review of 4 pediatric cases of mediastinal nontuberculous mycobacteria infection was undertaken. Each child presented with nonspecific respiratory symptoms, including significant acute airway obstruction and required a range of investigations to confirm the diagnosis. Nonresponsiveness to conservative measures and antimycobacterial therapy ultimately resulted in surgical intervention to obtain clinical improvement. Results: All 4 children had extensive evaluation and multidisciplinary involvement in otolaryngology, respiratory medicine, pediatric surgery, infectious diseases and cardiothoracic surgery. They all eventually had their disease debulked via thoracotomy in addition to prolonged antimycobacterial therapy, with successful clinical outcomes. Conclusions: Mediastinal nontuberculous mycobacteria infections in the pediatric population are rare and diagnostically challenging. A high clinical suspicion should be maintained, and multidisciplinary input sought. Targeted surgery with adjuvant medical therapy can reduce disease burden with minimal long-term morbidity.

N ontuberculous mycobacteria (NTM) are acid-fast bacilli (AFB) found throughout the environment, including in soil and tap water. 1 Mycobacterium avium complex (MAC) is responsible for 80% of all NTM infections. 2 NTM cases may be globally increasing due to improved diagnostics. 3The incidence varies geographically with the incidence in Australia ranging from approximately 0.6 to 1.6 cases per 100,000 children per year. 4In immunocompetent children, the most common manifestation of NTM is cervical lymphadenitis followed by skin and soft tissue infections. 2,5ediatric mediastinal lesions with airway involvement caused by MAC are exceedingly rare, accounting for 3.6% of all NTM cases in a recent Australian study. 4Pulmonary NTM tends to occur as lung parenchymal disease in children with underlying conditions such as cystic fibrosis, bronchiectasis or immunodeficiency. 4,5Intrathoracic NTM can occur in otherwise healthy children, confined to the mediastinal lymph nodes without significant pulmonary disease.The diagnosis can be elusive as bronchial washings are often negative and confirmation may require more invasive investigation.
Medical management of NTM lung infections has variable outcomes.Sputum clearance is often difficult to achieve, 6 and the combinations of antibiotics with known in vitro susceptibility do not necessarily correlate with clinical response.These antibiotics require prolonged administration and may be toxic, which can be challenging for children.Surgical debridement, debulking or excision can aid in making a definitive diagnosis and in disease resolution.However, these lesions are not always easily accessible and significant complications are possible. 7We present 4 children with mediastinal NTM infections where a multidisciplinary team (MDT) approach resulted in successful clinical outcomes.

Consent
Informed parental consent was obtained for publishing patient information and images.Ethics approval was gained through the Sydney Children's Hospital Network Research Ethics Office (CCR2021/06).

Case 1
A two-and-a-half-year-old immunocompetent male presented with a 3-month history of intermittent barking cough.The cough was not related to infectious upper respiratory symptoms or triggered by oral intake.He was well in between episodes though had developed soft airway sounds on exertion.He had been treated for presumed croup with oral dexamethasone and nebulized adrenaline a few times.Amoxicillin had had minimal effect.On presentation, he had increased work of breathing but no stridor or wheeze.His chest radiograph, full blood count and C-reactive protein were normal.His symptoms settled and he was discharged, however, he represented 2 weeks later with another episode.
Rigid laryngo-tracheo-bronchoscopy (LTB) identified a polypoidal growth at the distal right trachea causing near-complete obstruction of the right main bronchus (RMB).No foreign body or other abnormality was identified.A computerized tomography (CT) of the chest revealed a calcified right paratracheal mass ing into the airway (Fig. 1).A second right hilar mass was also seen.
The tracheal lesion was debulked endoscopically under a second general anesthetic.It was avascular and soft with a white-speckled internal appearance (Fig. 2).Histopathology demonstrated granulomatous inflammation.AFB were not identified on microscopy and culture.Molecular investigations on tissue, gastric aspirates and induced sputum did not yield bacterial, fungal or acid-fast isolates.His tuberculin skin test (TST) was 6 mm.An interferon-gamma release assay, immunology work-up including lymphocyte subsets, immunoglobulin levels and screening for chronic granulomatous disease, sarcoidosis and cystic fibrosis were negative.
Based on the radiologic features, NTM was the most likely diagnosis.However, the inability to identify the pathogen and its susceptibility made the choice, route and duration of medical treatment difficult, especially in the context of his age, compliance, tolerability and monitoring considerations.LTB 6 weeks later revealed regrowth of the mass to approximately 50% of its original size.A fluorodeoxyglucose positron emission tomographycomputerized tomography scan demonstrated the lesions to be metabolically active.
An MDT meeting with the infectious disease, respiratory, otolaryngology, pediatric and cardiothoracic surgical teams reached consensus for surgical debulking for diagnostic and therapeutic purposes.He underwent a right thoracotomy where a firm and adherent paratracheal nodal mass with its inferior border under the azygous vein was dissected out.Complete removal from the tracheal wall was not undertaken to avoid creating a significant defect.A second node was found at the hilum, inferior to the thymus with the phrenic nerve coursing posteriorly.Caseous material was curetted without damage to the phrenic nerve.MAC DNA was weakly detected by polymerase chain reaction (PCR) on intraoperative specimens.
Postoperatively, he was given triple antimycobacterial therapy (azithromycin, ethambutol and rifampicin) for 12 months.Followup chest CT 6 months after ceasing antibiotics showed significantly smaller areas of calcification with no endoluminal extension.Fluorodeoxyglucose positron emission tomography-computerized

Case 2
A 2-year-old, immunocompetent female presented to a regional hospital 3 times over 5 weeks with worsening cough, intermittent wheeze, increased work of breathing, loss of appetite and stagnant growth.The family had traveled to Malta 2 months prior.A chest radiograph demonstrated right upper and mid-zone changes with hyperinflation of the left lung.Flexible bronchoscopy performed locally identified a friable left main bronchial lesion.
LTB at our center revealed a fleshy obstructing mass within her eft main bronchus (LMB).The carina was splayed suggesting extrinsic compression from a mediastinal mass.Unexpectedly, the RMB was significantly narrowed by external compression, with only the right upper lobe bronchus patent.Maintaining ventilation was challenging, and extracorporeal membrane oxygenation was considered, however, she tolerated careful biopsy of the exophytic component.Chest CT demonstrated a homogenous hypoattenuating subcarinal mass 33 × 18 × 28 mm (Fig. 3A).An aggressive neoplastic lesion, lympho-vascular malformation or bronchogenic cyst were differential diagnoses.She was given high-dose intravenous methylprednisolone while awaiting biopsy results.
The biopsy revealed granulomatous inflammation but no evidence of malignancy.Flow cytometry, TST, GeneXpert PCR for Mycobacterium tuberculosis, pan-mycobacterial PCR, 3 gastric lavages, immunoglobulin levels, lymphocyte subsets, investigation for defects in the interferon-gamma pathway, Epstein-Barr virus and cytomegalovirus serology were all negative.
She was commenced on oral isoniazid, rifampicin and pyrazinamide.A repeat CT chest 2 weeks later revealed the subcarinal mass had decreased to 24 mm × 16 mm with reduced airway compression.When MAC was later confirmed from the initial bronchoalveolar lavage (BAL) cultures, she switched to clarithromycin, ethambutol and rifampicin.Nine weeks into treatment, however, she deteriorated with increased work of breathing and fatigue.A chest CT revealed almost complete obstruction of LMB, despite a reduction in size of the mass.
Following MDT discussion, the potential risk of surgical injury to the carina was raised hence a fourth antimycobacterial agent (intravenous amikacin) was added.Despite 3 months of treatment, the mass was compressing the RMB with hyperinflation of the right middle lobe on CT.She proceeded to surgical debulking via a right thoracotomy where a hard subcarinal nodal mass measuring 15 mm × 15 mm was firmly adherent to the esophagus.The trachea and RMB were defined, and the mass was resected without bronchial or esophageal injury.
Her antibiotic medications were continued for a total of 12 months.A follow-up chest CT 10 months after surgery revealed resolution of the subcarinal inflammatory lesion and normalization of the main bronchi (Fig. 3B).A chest radiograph at her local hospital 2 years after treatment was suggestive of residual nonobstructive mediastinal lymphadenopathy.She remains clinically well and asymptomatic at follow-up after 4 years.

Case 3
A two-and-a-half-year-old, previously well-female presented with an 18-month history of recurrent cough exacerbated by respiratory illnesses.She had been managed in the community with oral antibiotics, but had no response to bronchodilators.A chest CT revealed focal hyperdensity in the precarinal and subcarinal regions causing compression of the LMB, with the suggestion of calcified lymph nodes (Fig. 4).
Her TST reading was 20 mm.Panfungal, GeneXpert, pan-mycobacterial PCR of her sputum and 3 gastric lavages were negative for AFBs.Immunoglobulin levels, lymphocyte subsets, alpha-fetoprotein and beta-human chorionic gonadotrophin were normal.Flexible bronchoscopy and BAL showed no malignant cells, but revealed significant narrowing of the LMB.
She progressed to a left thoracoscopy with biopsy of the lesion.Dissection was difficult due to adhesions.The mass was deep under the aortic arch superior to the left pulmonary artery, under the ductus arteriosus and anterior to LMB.The LMB was inadvertently opened hence the procedure was converted to a left postero-lateral muscle-sparing thoracotomy.The mass was cleared from the bronchial defect to allow primary repair, then dissected from the pulmonary artery and aorta.Caseous, calcified material was curetted out, leaving the medial fibrous capsule in situ.
Histopathology showed granulomatous inflammation consistent with mycobacterial infection.AFB was not detected on

Case 4
A 14-month-old female presented to the emergency department with concern about upper airway obstruction and significant airway noise, possibly triggered by coryzal illness.She had a history of gastro-esophageal reflux disease, recurrent chest infections with wheeze treated as bronchiolitis, failure to thrive and gross motor delay.She had no improvement with fluticasone propionate.LTB revealed a slit-like RMB and chest CT showed a mediastinal soft tissue lesion without calcification, involving the subcarinal, right paratracheal and right hilar regions.There was mass effect on the left atrium, RMB and occlusion of the right middle lobe bronchus.
After MDT consultation, she underwent a thoracoscopy, which showed a posterior mediastinal mass tenting the azygous vein.Frozen section and formal histopathology of the lesion demonstrated granulomatous inflammation.She was treated with cefotaxime and dexamethasone however sputum from the endotracheal tube identified AFB.Although she had never traveled and there was no known exposure to M. tuberculosis, she was commenced on isoniazid, pyrazinamide, rifampicin, pyridoxine and prednisolone.She had a negative TST (0 mm).MAC (M.intracellulare) was later isolated on sputum culture and her medications were rationalized to clarithromycin, rifampicin, ciprofloxacin and ethambutol; the latter 2 medications were ceased after 6 months due to tolerance issues and potential neurotoxicity effects, and replaced with moxifloxacin.A gastrostomy tube was required for treatment delivery.
Speckled calcification of the affected nodes with infiltration into the airway lumen was apparent 18 months after the first CT scan (Fig. 5A).Flexible bronchoscopy and BAL 2 years after the initial presentation revealed 2 moderately large nodules on the medial wall of bronchus intermedius.Both lesions were ulcerated, bleeding and caseating.She remained on medications for a total of 3 and a half years, as there was slow resolution of her lymphadenopathy on imaging (Fig. 5B).LTB 1 year after ceasing treatment showed complete resolution of the lesions within the airway lumen.

DISCUSSION
Intrathoracic NTM disease confined to the mediastinal lymph nodes has historically been an unusual presentation in immunocompetent pediatric patients.MAC most commonly presents as cervical lymphadenitis, with current literature stating that except for patients with cystic fibrosis, children very rarely develop pulmonary disease 5,7,8 The diagnosis of mediastinal MAC infection in the pediatric population may be elusive.The clinical presentation varies  Mediastinal Mycobacterial Infection greatly, and children often present with nonspecific symptoms such as cough, weight loss, shortness of breath, wheeze, unexplained fevers and occasionally hemoptysis. 9Radiographic findings can include calcifications, isolated pulmonary nodules, mediastinal lymphadenopathy, parenchymal infiltrates or bronchial obstruction.Bronchoscopic findings range from normal anatomy, external compression through to lesions infiltrating the lumen.Microbiological and molecular confirmation of NTM from respiratory secretions or biopsies may not be reliable or sensitive in children, particularly in those with paucibacillary disease. 2 Histopathologic findings are likewise problematic to interpret, including nonspecific granulomatous inflammation that may be seen in NTM infection, but also in M. tuberculosis infection, fungal infections, brucellosis and melioidosis. 2he American Thoracic Society has proposed diagnostic criteria for adult NTM disease, incorporating the need for positive cultures on bronchial washings or sputum. 2 However, as in our cases, definitive positive cultures are exceptionally rare, especially in children. 5Additionally, these guidelines have not been validated for pediatric patients which adds to diagnostic uncertainty in this population subgroup.Litman et al 2 stated that the American Thoracic Society criteria may need to be altered when treating pediatric patients, as only 30%-50% of pediatric patients will have positive cultures on gastric aspirates.While BAL has improved the rates of diagnosis in adults, the clinical utility in children does not correlate. 2,9he challenge in making the diagnosis and recommending treatment necessitates collaborative input from otolaryngology, respiratory medicine, infectious diseases, pediatric surgery, cardiothoracic surgery, intensive care, and anesthetics.Mediastinal NTM should be considered early during an unusual soft tissue mass to prevent deterioration from significant airway obstruction, local destruction, invasion and involvement of critical mediastinal structures.Once other pathologies such as neoplastic processes have been excluded, a high index of suspicion based on the clinical and radiological findings should be maintained, as despite extensive investigation and sampling, microbiological confirmation of NTM may not occur or take a considerable length of time given its slow-growing nature.
Parental counseling and involvement are important in decision-making, particularly with regard to the tolerability of multiagent therapy, side effect monitoring requirements, suitability for surgery including access and risks, and modalities for surveillance.Controversy exists with regard to the management of mediastinal NTM in pediatric patients.The effectiveness and need for antimycobacterial therapy has not been well established in immunocompetent children. 5Current medical management is aggressive and requires a 3-or 4-drug regimen for 12 months, tailored to the species and susceptibility tests (if known).Empirical therapy often includes 3 drugs for the first 1 to 2 months, pending clinical and/or radiographic improvement.Typical regimens incorporate a macrolide (azithromycin or clarithromycin), ethambutol and a rifamycin (rifampin or rifabutin). 2,7Aminoglycosides or fluoroquinolone may be substituted or added as a fourth-line therapy for patients who develop breakthrough disease whilst receiving treatment, or for patients in whom there is concern about macrolide resistance.This is in line with the American Thoracic Society recommendations that indicate prolonged antimycobacterial therapy is necessary in adults with pulmonary infection caused by NTM; however, no standard therapeutic regimen is applicable to children. 5 Many of these drugs have known side effects, such as ototoxicity with prolonged amikacin use, QT prolongation or gastrointestinal effects.They may also be poorly tolerated and require frequent pathology tests, electrocardiograms, audiology testing and therapeutic drug monitoring.The children in our series were managed over a period of 14 years.Each had different social and medical considerations, which explains the variability in the choice of antibiotic therapy.
Surgery for mediastinal NTM may be necessary for diagnostic confirmation, to reduce disease burden, relieve airway obstruction, or when medical management is not effective.Options include removal or debulking of affected lymph nodes, lobectomy, segmentectomy, wedge resection or even pneumonectomy, the latter choices considered for extranodal disease. 10,11Shiraishi et al demonstrated 97% and 88% relapse-free rates at 5 and 10 years, respectively, when surgical resection was combined with pre-and post-operative anti-NTM medication. 12These findings are consistent with Lu et al who found that surgical excision provides higher rates of cure in patients with focal lung involvement with NTM.The surgical approach in their study was either via an anterior or posterior thoracotomy.Sputum clearance rates ranged from 84% to 100%, with better conversion rates if antibiotics were continued postoperatively. 10he decision to progress to surgery should be tailored to the individual.Surgical excision of an inflammatory mass lying adjacent to critical structures remains challenging, but debulking of disease is almost always necessary to achieve cure.Our cases had nodal disease adjacent to the trachea, carina and bronchi.Damage to these structures could have resulted in the need for challenging reconstruction and potentially prolonged intubation with extracorporeal membrane oxygenation support.MDT input was essential in the decision-making at several points in each patient's journey.
The best method and length of time for follow-up of pediatric mediastinal NTM has not been determined.NTM infections in sites like the cervical lymph nodes can be monitored with bedside assessment and ultrasounds, whereas intrathoracic disease surveillance is more challenging and likely to require general anesthesia and radiation exposure.Bronchoscopy, chest CT and magnetic resonance imaging were used in our patients depending on access to services, clinician and parental preference.Using different modalities for subsequent assessments can make comparison difficult.Mediastinal nodal changes remained present in our cohort, but were significantly improved over time, and stable for several years.The natural history and burnout of residual disease is unknown.All 4 of our patients have remained asymptomatic with no long-term morbidity and promising growth and development at the time of reporting.

CONCLUSION
Mediastinal NTM remains a rare clinical entity in children, posing a diagnostic challenge with variable and nonspecific clinical presentations.Furthermore, the administration of antimycobacterial medical therapy in this age group is not straightforward due to the prolonged course of multiple medications and the need for regular monitoring for potential toxicities.A high clinical suspicion should be maintained based on the clinical and radiological findings once other conditions have been excluded.Surgery is an effective adjunct to the treatment of NTM and should be considered early in the course of the disease, both for diagnostic and therapeutic purposes.Targeted rather than radical surgery can successfully reduce disease burden with minimal long-term morbidity.When surgery is combined with pre-and post-operative anti-NTM medications, disease control rates are high.However, the precarious location of the disease can make surgery high-risk.Our cases reveal

FIGURE 1 .
FIGURE 1. Noncontrast coronal CT scan of the chest showing a speckled hyper-dense right paratracheal lesion with contiguous extension into the distal right tracheal lumen (arrow) near the take-off of the right main bronchus (A).A second separate right parahilar lesion (arrow) had a similar speckled hyper-dense appearance (B).

FIGURE 2 .
FIGURE 2. Initial endoscopic view of the carina demonstrating a polypoid mass of the distal trachea causing near-complete occlusion of the entrance to the right main bronchus (A).Debulking using cupped forceps revealed a relatively avascular lesion with white spots and soft consistency (B).Clearance of the lesion flush to the lateral tracheal wall improved airflow to the right lung (C).

FIGURE 3 .
FIGURE 3. Coronal CT chest with contrast showing a large subcarinal mass causing external compression of the left and right mainstem bronchi as well as bronchus intermedius (A).Repeat CT chest 10 months following medical and surgical treatment (B).

FIGURE 4 .
FIGURE 4. Axial (A) and coronal (B) CT chest without contrast showing a mediastinal lesion with speckled calcifications causing anterior external compression of the left main bronchus.

FIGURE 5 .
FIGURE 5. Coronal CT chest with contrast (A) demonstrating a lesion in the right parahilar region eroding into the lumen of the right main bronchus despite being on treatment for 18 months.Repeat CT chest (B) 3 years after initial presentation showing normalization of the right main bronchus with some persistent minor calcifications.