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Nontuberculous mycobacterial lymphadenitis in children

Nontuberculous mycobacterial lymphadenitis in children
Author:
Andrea T Cruz, MD, MPH
Section Editor:
Morven S Edwards, MD
Deputy Editor:
Diane Blake, MD
Literature review current through: Jan 2024.
This topic last updated: Feb 08, 2023.

INTRODUCTION — Nontuberculous mycobacteria (NTM) are a miscellaneous collection of acid-fast bacteria that are widespread in the environment [1]. They have been isolated from numerous environmental sources, including water, soil, food products, and domestic and wild animals [2]. Health care-associated transmission has occurred with medical equipment [3-5].

This topic will provide an overview of NTM lymphadenitis in children. NTM skin and soft tissue infections, pulmonary infections, disseminated infections, and bacteremia in children are discussed separately.

(See "Nontuberculous mycobacterial skin and soft tissue infections in children".)

(See "Nontuberculous mycobacterial pulmonary infections in children".)

(See "Disseminated nontuberculous mycobacterial (NTM) infections and NTM bacteremia in children".)

MICROBIOLOGY — More than 170 species of nontuberculous mycobacterial (NTM) have been identified, not all of which have been documented to cause disease in humans [6-9].

Classification – NTM pathogens are classified as rapidly growing or slowly growing (table 1). Rapidly growing species grow within seven days and include Mycobacterium fortuitum, Mycobacterium abscessus, Mycobacterium chelonae, Mycobacterium smegmatis, and Mycobacterium mucogenicum. Slowly growing species require several weeks to grow and include Mycobacterium avium complex (MAC), Mycobacterium marinum, and Mycobacterium kansasii. (See "Microbiology of nontuberculous mycobacteria", section on 'Classification'.)

Disease associations – NTM can cause a broad range of infections that vary depending on the particular NTM species and the host. In children, NTM cause four main clinical syndromes: lymphadenitis, skin and soft tissue infection, pulmonary disease (predominantly in children with underlying pulmonary conditions), and disseminated disease (predominantly in children with immune compromise).

In case series of nontuberculous mycobacterial lymphadenitis among children in the United States, the majority of cases occur in previously healthy children and are caused by MAC, which includes M. avium and Mycobacterium intracellulare [2,10,11]. In series from other countries, MAC and Mycobacterium haemophilum are frequently isolated [12-18].

EPIDEMIOLOGY — Estimates of the true burden of nontuberculous mycobacterial (NTM) infections in children are unavailable; in part because NTM infections may be asymptomatic and because NTM infections are not communicable, reporting of NTM infections is not required in the United States or many other countries [2]. Nonetheless, the overall prevalence of NTM disease appears to be increasing (possibly as a result of enhanced detection) [10,19-22]. (See "Epidemiology of nontuberculous mycobacterial infections".)

In population-based surveillance studies, estimates of the annual incidence of NTM in children range widely: from 0.6 to 1.6 per 100,000 children in Australia, to 3.1 per 100,000 children in Germany, to 77 per 100,000 children in the Netherlands [23-26]. In each of these studies, lymphadenitis was the most common presentation. In a multicenter case series from Germany and Austria, children with NTM lymphadenitis were more likely to seek treatment during the colder months [27].

NTM are transmitted through environmental sources. M. avium complex (MAC), the most common cause of lymphadenitis, is found in soil and water (from both natural and treated water) [28-32]. Aquatic transmission of NTM is facilitated by the formation of biofilms, which permit survival under a variety of environmental conditions and allow dissemination of large numbers of organisms when they become detached [33]. In surveillance from Australia, where reporting of NTM species is mandatory, M. haemophilum infections in children increased following episodes of severe flooding [18].

Children with a history of bacille Calmette-Guérin (BCG) immunization appear to have a reduced risk of MAC lymphadenitis [34]. Conversely, the risk NTM infection, including NTM lymphadenitis, appears to increase following countrywide discontinuation of mandatory BCG immunization [17,35-37].

The oropharyngeal mucosa is the typical portal of entry for NTM cervical lymphadenitis. Lymphadenitis in other sites may follow penetrating trauma [10,38].

The incubation periods are variable [9].

CLINICAL FEATURES — Lymphadenitis is the most common manifestation of nontuberculous mycobacterial (NTM) disease in childhood. It typically occurs in children between one and five years of age [10,13,26,39]. The cervicofacial nodes, particularly the submandibular nodes, are most frequently involved [10,18,26,40]. Lymph nodes outside the head and neck, including hilar or mediastinal nodes, may also be involved. Some children have associated odontogenic infections and/or a history of recent dental care or procedures [41]. Outbreaks of NTM infections have been reported among children who underwent dental procedures in clinics where the dental treatment water contained high levels of bacteria [42,43].

NTM lymphadenitis generally presents as a unilateral, nontender node (<4 cm in diameter) that slowly enlarges over several weeks [44]. Lymph nodes enlarge in the path of least resistance, often becoming tethered to the overlying skin. The overlying skin then gradually changes from pink to violaceous and thins to become parchment-like (picture 1) and may eventually suppurate through a sinus tract [1,10,26,44]. Sinus tract formation can occur spontaneously or follow direct trauma to the region. Fever and other systemic findings are variable and are more common if the lymph nodes become secondarily infected by pyogenic bacteria (eg, staphylococcal or streptococcal species) [24,25]. If prescribed, antibiotics directed against staphylococci or streptococci generally are not helpful [1,22,44,45]. These features do not reliably differentiate NTM from Mycobacterium tuberculosis lymphadenitis. (See 'Differential diagnosis' below.)

Delay in diagnosis is common. In a series of 105 patients, the time between onset of swelling and diagnosis was typically four to eight weeks (median 6.5 weeks, range eight days to two years) [10].

The clinical features of NTM lymphadenitis have been described in several case series, each including >100 children [10,24,26,39]:

The submandibular nodes were involved in 87 percent, followed by preauricular (9 percent) and submental (3 percent) nodes; supraclavicular node involvement was uncommon [39].

Nearly all cases of cervical adenitis were unilateral (89 to 99 percent) [10,24,39].

Violaceous discoloration and fluctuance were present in 85 percent [39] but often are not present at the time lymphadenopathy is first noted.

Fever (temperature >38.5°C [101.3°F]) was present in 13 to 21 percent [24,26].

In one series, a fistula developed in 14 of 84 patients (16.7 percent) [24]; in another, a draining sinus tract was noted on follow-up ultrasonography in 62 of 66 (93 percent) patients who were initially treated with antibiotics but without excision [39].

Development of a fistula often is preceded by fluctuance in the node, thinning of the overlying skin, and tethering of the node to the skin.

Lymph nodes in addition to those in the cervicofacial region were involved in 15 percent of cases in one series (86 percent of such cases were caused by M. haemophilum, 14 percent by M. avium) and 29 percent in another [10,39].

RADIOGRAPHIC FEATURES — Imaging studies are not necessary in the routine evaluation of a child with suspected nontuberculous mycobacterial (NTM) adenitis but may be helpful in evaluating other conditions in the differential diagnosis of cervical adenitis [46]. (See "Cervical lymphadenitis in children: Diagnostic approach and initial management" and "Cervical lymphadenitis in children: Etiology and clinical manifestations".)

Ultrasonographic features of NTM lymphadenitis were described in case series in which ultrasonography was performed on 145 children who participated in a clinical trial [39]. Early in the disease course, decreased echogenicity was noted in all patients; in the advanced stages, 92 percent had intranodal liquefaction, matted nodes, and soft tissue edema. In a case series of 138 children with NTM lymphadenitis, intranodal liquefaction was strongly associated with unfavorable outcome (defined as symptoms lasting >12 months, requiring >1 surgical intervention, facial nerve palsy, major complications, or substantial scarring) [27].

Computed tomography findings of NTM lymphadenitis include ring enhancement with central hypodensity and minimal to absent fat stranding; the lack of fat stranding may help to differentiate NTM from pyogenic lymphadenitis [39,47,48].

Chest radiograph (frontal and lateral) may be performed to look for signs of pulmonary tuberculosis or malignancy (eg, hilar adenopathy). The lateral radiograph is particularly important in young children in whom the thymic silhouette may obscure assessment of the mediastinum on the frontal view. The chest radiograph is typically normal in children with NTM lymphadenitis [2,49].

LABORATORY FEATURES — Children with nontuberculous mycobacterial (NTM) lymphadenitis usually have normal complete blood count (CBC), differential, and erythrocyte sedimentation rate (ESR) [19,26]. Abnormal findings in the CBC and/or elevated ESR should prompt consideration of other conditions in the differential diagnosis. (See "Cervical lymphadenitis in children: Etiology and clinical manifestations" and "Cervical lymphadenitis in children: Diagnostic approach and initial management".)

Histopathology and acid-fast bacilli stains are discussed below. (See 'Microbiology and histopathology' below.)

DIAGNOSIS

Clinical suspicion — Nontuberculous mycobacterial (NTM) lymphadenitis should be suspected in young children (<5 years) with subacute/chronic (ie, weeks to months), unilateral, nontender, cervicofacial lymphadenitis that fails to improve or worsens despite antibiotic therapy directed against staphylococci and streptococci (if such therapy has been provided) [1]. Patients are usually well appearing without constitutional symptoms.

The clinical course and appearance of NTM adenitis, particularly when the overlying skin becomes violaceous and thin, often is so characteristic that a presumptive diagnosis can be made based upon the history and physical examination (picture 1) [1]. (See 'Clinical features' above.)

However, early in the course of disease, particularly before the skin becomes violaceous, other conditions in the differential diagnosis may appear more likely, and evaluation and treatment for such conditions may be undertaken before NTM is suspected. This evaluation may include complete blood count with differential and erythrocyte sedimentation rate, tuberculin skin testing (TST), interferon gamma release assay (IGRA), imaging, and/or serologic testing (as clinically indicated for Bartonella henselae, Epstein-Barr virus, cytomegalovirus, human immunodeficiency virus [HIV], toxoplasmosis, etc). (See "Cervical lymphadenitis in children: Diagnostic approach and initial management", section on 'Subacute/chronic'.)

Preliminary differentiation from M. tuberculosis — It is particularly important to try to distinguish between NTM and M. tuberculosis lymphadenitis because they have different public health and treatment implications [2]. Although detection of NTM with culture or polymerase chain reaction (PCR) assay is necessary for definitive diagnosis, the TST and IGRAs may be helpful in differentiating NTM from M. tuberculosis [50]. TST and IGRA are typically performed on the same day (algorithm 1).

The TST contains numerous antigens shared by M. tuberculosis and NTM species. IGRAs are in vitro blood tests of cell-mediated immune response; they measure T cell release of interferon-gamma following stimulation by antigens unique to M. tuberculosis [51]. They do not cross react with the NTM species that most frequently cause lymphadenitis (M. avium complex [MAC], M. haemophilum, Mycobacterium scrofulaceum) or with bacille Calmette-Guérin (BCG) immunization (which uses an attenuated form of Mycobacterium bovis), but they may cross react with other NTM species, including M. marinum, Mycobacterium szulgai, M. kansasii, Mycobacterium flavescens, wild type M. bovis, Mycobacterium gastri, and Mycobacterium riyadhense [52,53]. The TST and IGRAs are discussed in greater detail separately. (See "Tuberculosis infection (latent tuberculosis) in children", section on 'How to test'.)

The interpretation of TST and IGRA in children with lymphadenitis depends upon the size of induration, risk factors for M. tuberculosis (eg, contact with a person with M. tuberculosis disease, residence in or travel to an area where M. tuberculosis is endemic), and receipt of BCG vaccination. In immunocompromised children, the sensitivity of TST and IGRA is decreased, and results should be interpreted with caution [54].

TST with ≥5 mm induration TST with ≥5 mm of induration at 48 hours may be due to NTM (usually in children without risk factors for M tuberculosis), M. tuberculosis (usually in children with risk factors for M. tuberculosis), or false positive result from BCG immunization (if the child received BCG) [2,12,46,50,55]. TST ≥15 mm may be more suggestive of M. tuberculosis than NTM but does not exclude NTM or reaction to BCG. IGRA results may help to differentiate between these possibilities (algorithm 1) [56].

Positive IGRA suggests M. tuberculosis [50].

Negative IGRA suggests either:

-NTM in children who have not received BCG.

In a study of 174 children with cervicofacial lymphadenitis who had no exposure to M. tuberculosis and had not received BCG vaccination, TST with >5 mm of induration at 48 hours had a sensitivity of 70 percent, specificity of 98 percent, positive predictive value of 98 percent, and negative predictive value of 64 percent for NTM (confirmed by positive culture and/or PCR) [12].

-False positive TST related to BCG immunization if the child received BCG; IGRAs do not interact with the attenuated form of M. bovis that is used in BCG immunization.

Indeterminate IGRA does not help differentiate NTM from M. tuberculosis.

TST with no induration or induration of <5 mm – TST with no induration or induration of <5 mm at 48 hours does not exclude mycobacterial disease. In these children (algorithm 1):

Positive IGRA suggests M. tuberculosis.

Negative or indeterminate IGRA may indicate either NTM (in a child with characteristic clinical features such as violaceous discoloration and thinning of the skin or a fistulous tract) or an alternate diagnosis. (See 'Other conditions' below.)

Laboratory confirmation

Obtaining and processing specimens — Specimens for microbiologic and histopathologic studies in children with suspected NTM may be obtained through excisional biopsy, fine needle aspiration (FNA), or fistulous drainage. If there is a strong suspicion of NTM, excisional biopsy often is undertaken because it is curative; in addition, the yield is usually better than with FNA because more tissue is available for culture. FNA can increase microbiologic yield when excisional biopsy may not be an option (eg, proximity of the affected node to the facial nerve) and is infrequently associated with fistulous complications [1,2,47,57]. However, some advocate FNA for obtaining diagnostic material [13,58]. FNA cytology can rapidly provide accurate information and has excellent concordance with biopsy samples sent for culture [57]. (See 'Management' below.)

Incision and drainage generally are contraindicated if NTM is suspected because of the risk of recurrence or development of a chronically draining fistula [1,59-62]. However, incision and drainage may have been performed before NTM was suspected. (See "Cervical lymphadenitis in children: Diagnostic approach and initial management".)

It is helpful to discuss specimen collection, transport, and processing with the microbiology laboratory before sending tissue or fluid samples for suspected NTM. Swabs of tissue or fluid samples have lower culture yield and are not recommended [63]; preferred samples include tissue samples or nodal fluid. Some species of NTM (eg, M. haemophilum) have fastidious growth requirements.

Microbiology and histopathology — Detection of NTM in culture or PCR of fistula drainage, tissue, or caseous material confirms the diagnosis of NTM lymphadenitis [1,2,10,19]. Tissue specimens and/or aspirated fluid or pus should be sent for mycobacterial culture, PCR, acid-fast bacilli (AFB) stains, and histopathology (in addition to bacterial and fungal stains and cultures, and cytopathology as clinically indicated).

Pending culture results or if NTM is not detected, positive AFB stains and characteristic histopathology can help to establish a presumptive diagnosis in children with characteristic clinical features (eg, subacute/chronic unilateral lymphadenitis, violaceous discoloration) if other conditions in the differential diagnosis have been excluded [1,10,19,47,58].

Mycobacterial culture – A positive culture confirms the diagnosis of NTM lymphadenitis. However, isolation and identification of the NTM species may take longer than six weeks [12]. The yield of positive NTM cultures from excised lymph nodes ranges from 50 to 80 percent [2,10]. The yield is usually lower for specimens obtained through FNA, though yields of up to 80 percent have been reported [13]. Microbiologic techniques to maximize the yield of NTM cultures are discussed separately. (See "Microbiology of nontuberculous mycobacteria", section on 'Culture'.)

Among children with a negative culture or in whom culture results are pending, a presumptive diagnosis of NTM lymphadenitis can be made if the clinical (eg, subacute/chronic nontender, unilateral lymphadenitis, violaceous discoloration) and/or histopathologic features (eg, positive stains for AFB, granulomas) are compatible with NTM and other conditions in the differential diagnosis (including M. tuberculosis) have been excluded [1,10,19,47,58]. (See 'Clinical features' above and 'Laboratory features' above and 'Differential diagnosis' below.)

PCR – The diagnosis of NTM infection can be established with species-specific or multiplex PCR testing [2,64-66]. PCR tests that can identify MAC soon after growth is evident are commercially available [67]. In a study of 67 children with mycobacterial adenitis and 50 children with cat scratch disease, the sensitivity and specificity of mycobacterial PCR were 72 and 100 percent, respectively [64]. The performance of PCR is based upon the quality of the specimen. Sending lymphatic tissue for culture and molecular testing is superior to sending exudative material.

AFB stains and histopathology

Features – Histopathologic features of NTM lymphadenitis include caseating granulomas, necrotizing granulomas, granulomatous and pyogenic inflammation, mononuclear inflammation, fibrocaseous reactions, multinucleated giant cells, and microabscesses [10,47,68]. These histologic features overlap with those of M. tuberculosis. (See "Microbiology of nontuberculous mycobacteria", section on 'Microscopy'.)

Interpretation – Although positive stains for AFB and histopathology with characteristic features support a diagnosis of mycobacterial infection, positive AFB stains do not distinguish among NTM species or between NTM species and M. tuberculosis. In addition, positive AFB staining in children with NTM lymphadenitis is variable. Negative AFB stains do not exclude mycobacterial disease.

Subsequent evaluation — In a previously healthy child, detection of an NTM species in a lymph node is not an indication for routine immunologic evaluation. Most cases of NTM lymphadenitis occur in immunocompetent children.

Immunologic evaluation may be warranted for children with NTM lymphadenitis who have recurrent, deep, or systemic NTM infections; systemic symptoms at the onset of lymphadenitis; NTM lymphadenitis outside the head and neck region; or a family history of consanguinity and/or infant deaths [69]. Cervicofacial lymphadenitis has been associated with FCHO1 deficiency (a novel type of combined immunodeficiency impaired T-cell proliferation, among other defects) and Mendelian susceptibility to mycobacterial diseases. (See "Mendelian susceptibility to mycobacterial diseases: An overview", section on 'Presentation and clinical features' and "Mendelian susceptibility to mycobacterial diseases: Specific defects" and "Combined immunodeficiencies: Specific defects", section on 'FCHO1 deficiency'.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of nontuberculous mycobacterial (NTM) lymphadenitis includes other infectious causes of unilateral lymphadenitis (eg, Staphylococcus aureus, Streptococcus pyogenes, B. henselae, M. tuberculosis, viral infections, toxoplasmosis), benign cysts, and malignancy [1,10,49,70]. Historical, examination, and laboratory findings (eg, blood counts, erythrocyte sedimentation rate, serology) may be helpful in differentiating NTM lymphadenitis from these conditions. (See "Cervical lymphadenitis in children: Etiology and clinical manifestations" and "Cervical lymphadenitis in children: Diagnostic approach and initial management".)

M. tuberculosis — It is particularly important to try to distinguish between NTM and M. tuberculosis lymphadenitis because they have different public health and treatment implications [2]. Culture is necessary for definitive diagnosis. (See 'Preliminary differentiation from M. tuberculosis' above and "Tuberculous lymphadenitis", section on 'Cervical lymphadenopathy'.)

No clinical or histopathologic feature reliably differentiates NTM from M. tuberculosis lymphadenitis. However, in observational studies, certain features were more suggestive of NTM [11,49,68]. These include:

Younger age (eg, preschool)

Lack of risk factors for tuberculosis, including being born in a country with low prevalence of M. tuberculosis

Normal chest radiograph

Negative tuberculin skin testing (TST) results in family members

Negative interferon gamma release assay

Ill-defined (nonpalisading), irregular, serpiginous, or sarcoid granulomas

Polymorphonuclear leukocytes in center of areas of necrosis rather than diffusely scattered

Lack of significant caseation

Microabscesses

Other conditions — In contrast to lymphadenitis due to other bacterial pathogens, NTM lymphadenitis has a more subacute/chronic course, lacks warmth and tenderness, and often has overlying violaceous skin discoloration; TST testing may be positive, but other laboratory findings usually are normal. (See 'Clinical features' above and "Cervical lymphadenitis in children: Etiology and clinical manifestations" and "Cervical lymphadenitis in children: Diagnostic approach and initial management".)

MANAGEMENT — The management of nontuberculous mycobacterial (NTM) lymphadenitis in children may require surgery and/or antimycobacterial therapy, in combination or sequentially. When discussing the benefits and risks of these modalities, caregivers should be advised that clinical response to both surgical and medical management may be incomplete and additional procedures and therapies may be necessary [40]. If the diagnosis is uncertain and the surgical risks (eg, facial nerve injury) preclude surgical excision, fine needle aspiration (FNA) may help establish the microbiologic diagnosis with minimal procedural risk. (See 'Laboratory confirmation' above.)

Surgical excision (preferred)

Indications – For patients with NTM or suspected NTM lymphadenitis and no evidence of pulmonary or disseminated disease, we suggest surgical excision without antimicrobial therapy as the initial intervention if complete excision can be performed safely (eg, without damage to the facial nerve (figure 1)). The risk of injury to the facial nerve is increased in children with preauricular or intraparotid involvement. Surgical excision is curative and provides the optimal specimen for diagnostic testing [1,2,40,71-75]. Incision and drainage generally are contraindicated because of the high probability of developing a chronically draining sinus tract and increased risk of recurrence [1,59-62]. The management of pulmonary and disseminated NTM disease in children is discussed separately. (See "Nontuberculous mycobacterial pulmonary infections in children", section on 'Treatment' and "Disseminated nontuberculous mycobacterial (NTM) infections and NTM bacteremia in children", section on 'Treatment'.)

In a randomized trial and observational studies, surgical excision has been associated with higher rates of cure, improved/more rapid healing, better cosmetic results, and fewer adverse effects than curettage, antimycobacterial therapy, or observation [1,26,45,71,72,74,76]. In a meta-analysis of randomized and observational studies including >1900 children with NTM lymphadenitis, the adjusted mean cure rate was greater for complete surgical excision (98 percent, 95% CI 97-99.5 percent) than for curettage (88 percent, 95% CI 70-97 percent), antimycobacterial therapy (73 percent, 95% CI 50-88 percent), or observation (70 percent, 95% CI 40-89 percent) [40]. The rates of fistula formation were also lower with complete surgical excision than other interventions (2 versus 19 percent with curettage, 4 percent with antimycobacterial therapy, and 60 percent for observation). In one of the included trials, wound healing was shorter with excision than curettage (3.6 versus 11.4 weeks) [74].

A randomized trial compared surgical excision with antimycobacterial therapy (clarithromycin and rifabutin for at least 12 weeks and up to six months) in 100 children with NTM lymphadenitis (M. avium complex [MAC] was isolated in 71 percent; all of the isolates were macrolide susceptible) [72]. The rate of cure (defined as regression of the lymph node enlargement by at least 75 percent, cure of the fistula, and total skin closure without local recurrence or de novo lesions after six months) was greater in the excision group (96 versus 66 percent). Surgical complications (wound infection, postoperative hematoma, facial nerve palsy) occurred in 28 percent of children in the excision group, while 78 percent of children in the antimycobacterial therapy group had adverse effects related to medication or disease progression.

Complications – Facial nerve palsy is an important complication of complete excision. Among 1077 children in the meta-analysis who underwent complete excision, transient facial nerve palsy occurred in 8 percent and permanent facial nerve palsy in 2 percent, compared with none of the children who were managed with curettage, antimycobacterial therapy, or observation [40]. Less common complications of complete excision included fistula formation (2 percent), wound infection (2 percent), scar formation (2 percent), and additional intervention (8 percent).

Postoperative follow-up — Children with isolated NTM lymphadenitis that has been successfully excised can be discharged from follow-up when their wound is healed. However, they should be informed that there is a small (<5 percent) risk of recurrence or development of new lesions [72] and instructed to return to medical attention if they notice any changes in the lesion. Recurrences may be treated surgically or with antimycobacterial therapy.

Antimycobacterial therapy

Indications – For children with isolated NTM lymphadenitis or suspected NTM lymphadenitis who are not candidates for surgical excision (eg, increased risk of facial nerve damage [eg, preauricular or intraparotid involvement (figure 1)] or poor cosmetic result, established sinus tract, etc), we suggest antimicrobial therapy with or without subsequent gentle curettage rather than observation (ie, wait and see). The prolonged course of spontaneous resolution may make observation intolerable for some families [13,77]. (See 'Observation' below.)

Randomized and observational studies indicate that antimicrobial therapy, usually with a macrolide and another agent, has moderate success in clearing the lymphadenitis without surgical excision (resolution rates range from 50 to 100 percent) [47,72,74,77-81]. However, patients who are treated with antibiotics alone may develop fistulous sinus tracts [72]. In a meta-analysis of randomized and observational studies, among 171 children treated with antimycobacterial therapy, the adjusted mean cure rate was 73 percent (95% CI 50-88 percent); 4 percent developed fistulas and 31 percent required additional surgical intervention [40].

In a randomized trial that directly compared surgical excision with antimycobacterial therapy (clarithromycin and rifabutin for at least 12 weeks and up to six months), 66 percent of patients treated with antibiotics were cured (defined as regression of the lymph node enlargement by at least 75 percent, cure of the fistula, and total skin closure without local recurrence or de novo lesions after six months), 32 percent developed draining fistula, and 78 percent had adverse effects related to medication or disease (eg, fever, fatigue, abdominal pain, tooth discoloration, headache, vomiting) [72]. It is important to warn caregivers about the possibility of developing a draining fistula before starting antimycobacterial therapy.

In another randomized trial that directly compared observation and antimycobacterial therapy (clarithromycin and rifabutin for 12 weeks) in 50 children with advanced NTM lymphadenitis (ie, fluctuance and skin discoloration), the median time to resolution was similar between groups (approximately 38 weeks) [77]. In follow-up of at least two years, no recurrences were reported. In a subsequent observational study of children with NTM lymphadenitis who did not undergo surgery, median time to resolution was shorter with antibiotic therapy (rifabutin plus a macrolide) than observation (24 versus 44 weeks) [82]. Ten children (eight in the observation group and two in the antibiotic therapy group) had recurrence at the same site during the 10-year follow-up period. Recurrence occurred in the first year after healing in three patients, in the second year in four patients, and later in three patients.

In observational and randomized trials, fistula formation is less common in children who are treated with antibiotic therapy than with observation (4 versus 60 to 70 percent) [40,83].

Regimen and duration – The empiric antimycobacterial regimen is determined by the likely causative species. The majority of NTM lymphadenitis is caused by MAC [11,12]. In the United States, Mycobacterium simiae and M. fortuitum are less common causes [11]. M. haemophilum is more commonly detected in the Netherlands and other countries [12-15].

The optimal duration of antimycobacterial therapy for lymphadenitis is unknown; patients typically are treated until their symptoms resolve (usually within three to six months) [19,72].

MAC – Given the predominance of MAC in pediatric cervicofacial lymphadenitis, when antimicrobial treatment for NTM lymphadenitis is undertaken, and M. tuberculosis is not a concern, we suggest empiric therapy with a macrolide (azithromycin or clarithromycin) in combination with ethambutol and/or rifampin (or rifabutin) (table 2) [2,9].

This regimen is suggested based upon those in randomized trials, observational studies, and in vitro studies, with the caveat that, with the exception of macrolides and MAC, there is poor correlation between in vitro susceptibilities and clinical outcomes [26,47,72,78,80,81]. Our suggested regimen is consistent with the recommendations of the American Thoracic Society, IDSA, and the AAP Committee on Infectious Diseases [2,9].

Clarithromycin was used in early studies of MAC lymphadenitis; however, azithromycin may be preferable because it is more palatable and is dosed once per day [84,85]. Although MAC is usually susceptible to macrolides, single-drug therapy with a macrolide increases the risk of development of mutational resistance [2].

M. tuberculosis not excluded – For children with suspected NTM lymphadenitis in whom M. tuberculosis remains a concern (eg, pending culture or polymerase chain reaction assay results in children with risk factors for M. tuberculosis), the empiric antimicrobial regimen should include coverage for both NTM and M. tuberculosis. For preschool children who are more likely than older children to have NTM lymphadenitis and who may not tolerate the volume of medication required for combination therapy with five drugs, an appropriate regimen includes isoniazid, rifampin, ethambutol, and a macrolide (either azithromycin or clarithromycin) (table 2). For older children, pyrazinamide is added [86].

The antibiotic regimen may need to be altered when definitive speciation is available. (See "Tuberculosis disease in children: Treatment and prevention".)

Suspected or confirmed non-MAC species – The antibiotic regimen may need to be altered if a species other than MAC is suspected or confirmed.

-M. simiae – The optimal therapeutic regimen for M. simiae has yet to be determined [2]. Agents that appear to be active in vitro include clarithromycin, rifabutin, clofazimine (not available in the United States), streptomycin, and moxifloxacin (table 3) [87].

-M. fortuitum M. fortuitum typically is susceptible to macrolides, amikacin, carbapenems, fluoroquinolones, and trimethoprim-sulfamethoxazole (table 3) [2,88-93]. Single-agent therapy with a macrolide is not recommended because M. fortuitum has inducible macrolide resistance [94].

-M. haemophilum – The optimal therapeutic regimen for M. haemophilum has yet to be determined [2]. Agents that appear to be active in vitro include amikacin, clarithromycin, ciprofloxacin, and rifamycins (table 3) [95-99].

Adverse effects – The antimycobacterial agents that are used to treat NTM lymphadenitis often are difficult to tolerate, and some have important toxicities. Important adverse effects include (but are not limited to) ototoxicity and nephrotoxicity with amikacin and streptomycin, optic neuropathy with ethambutol, and hepatotoxicity with isoniazid (table 3). The adverse effects of the agents used to treat NTM infections are discussed in greater detail separately. (See "Pathogenesis and prevention of aminoglycoside nephrotoxicity and ototoxicity" and "Manifestations of and risk factors for aminoglycoside nephrotoxicity" and "Ethambutol: An overview" and "Azithromycin and clarithromycin", section on 'Adverse reactions' and "Rifamycins (rifampin, rifabutin, rifapentine)" and "Isoniazid: An overview" and "Isoniazid hepatotoxicity" and "Aminoglycosides", section on 'Toxicity'.)

Adjunctive surgical therapy – FNA may help to decompress a large, fluctuant lymph node and may be warranted if the risk of developing a draining sinus tract is high (eg, central fluctuance with extension towards the skin, increased risk of paradoxical worsening after initiation of antimycobacterial therapy [eg, adolescent or young adult male]) [100].

Curettage may be indicated for children with bulky lymphadenopathy in whom surgical excision is not possible (eg, the node encompasses the facial nerve) but it is desirable to decrease the size of the lymph node (eg, to improve lateral rotation of the neck, to decrease the area of abscessed lymph nodes with poor penetration of antibiotics).

Response to therapy – The response to antimicrobial therapy for NTM lymphadenitis is monitored clinically. We suggest follow-up visits at approximately monthly intervals to ensure that patients are taking and tolerating their medications (if prescribed) and that their lymphadenitis is improving.

Treatment failure – There is no standard definition for treatment failure. We consider patients who have no improvement of symptoms after six months of therapy or who have progression of symptoms during therapy to have treatment failure.

For children who are not responding to what should be effective therapy, it is important to verify speciation and susceptibility testing and to make sure that the child has received antimycobacterial therapy as prescribed, recognizing that with the exception of macrolides and MAC, there is poor correlation between in vitro susceptibilities and clinical outcomes.

Surgical excision, if it can be safely performed, may be warranted for patients who fail to improve or worsen during antimicrobial therapy for NTM lymphadenitis. (See 'Surgical excision (preferred)' above.)

For patients who are not surgical candidates, a change in the antimicrobial regimen and/or testing for clarithromycin resistance may be warranted [2].

Observation — We usually suggest against observation for children with NTM lymphadenitis, but it may be a feasible approach for caregivers wishing to avoid surgery. Given enough time, children with isolated NTM lymphadenitis will have resolution of disease without treatment [13,70,77,82]. In an observational study of 92 children with NTM cervical lymphadenitis and minimal disease (eg, single node involvement, only 25 percent with skin changes), resolution of symptoms occurred within 6 months in 71 percent, within 9 months in 25 percent, and within 12 months in 2 percent [13]. Purulent drainage lasted three to five weeks in 91 percent and eight weeks in 5 percent.

Although resolution eventually occurs, many children with untreated NTM lymphadenitis develop sinus tracts with prolonged drainage [10,40,77], and caregivers/patients may not be willing to tolerate a draining lesion on the face or neck for the six months (or longer) that may be required for spontaneous healing [13,73]. In addition, recurrence is more common among children treated with observation [83]. Nonetheless, in a cohort of 21 children with confirmed craniofacial NTM cervical lymphadenitis managed by observation alone whose caregiver completed a satisfaction questionnaire at a median of 6.8 years after presentation, all but one respondent expressed contentment with observation alone as a management strategy [101].

In a meta-analysis of randomized and observational studies, among 157 children with NTM lymphadenitis who were managed with observation, the adjusted mean cure rate was 70 percent (95% CI 40-89 percent); 60 percent developed fistulas, 2 percent developed scars, and 3 percent required surgical intervention [40]. In a long-term follow-up study (median 6.8 years, range 2.3 to 16.9 years) of 21 children with craniofacial NTM lymphadenitis, 18 patients had ≥1 scar; most of the scars were <3 cm in length with normal pigmentation and a normal or only mildly uneven surface [101].

MANAGEMENT OF RECURRENCE — There is limited evidence to guide treatment of recurrent nontuberculous mycobacterial (NTM) lymphadenitis following surgical excision or antimicrobial therapy. In clinical trials and observational studies, recurrent NTM lymphadenitis has been successfully treated with surgical excision (if it can be performed safely) or antimycobacterial therapy [72]. (See 'Surgical excision (preferred)' above and 'Antimycobacterial therapy' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Nontuberculous mycobacteria".)

SUMMARY AND RECOMMENDATIONS

Microbiology – Lymphadenitis is the most common manifestation of nontuberculous mycobacterial (NTM) disease in otherwise healthy children. Most cases of NTM lymphadenitis in the United States are caused by Mycobacterium avium complex (MAC). Other commonly detected species include Mycobacterium haemophilum, Mycobacterium simiae, and Mycobacterium fortuitum. (See 'Introduction' above and 'Microbiology' above.)

Clinical findings – NTM lymphadenitis usually occurs in immunocompetent children between one and five years of age and involves the cervicofacial lymph nodes. It typically begins as a unilateral, nontender node that slowly enlarges over several weeks, during which fluctuance, violaceous discoloration, thinning of the overlying skin, and sinus drainage may develop (picture 1). (See 'Clinical features' above.)

Children with NTM lymphadenitis generally have normal complete blood count, differential, erythrocyte sedimentation rate, and chest radiograph. (See 'Laboratory features' above and 'Radiographic features' above.)

Evaluation and diagnosis – Definitive diagnosis requires detection of NTM with culture or polymerase chain reaction assay of fistula drainage, tissue, or caseous material. A presumptive diagnosis can be made if the clinical (eg, subacute/chronic unilateral lymphadenitis, violaceous discoloration) and/or histopathologic features (eg, positive acid-fast bacilli stains, granulomas) are compatible with NTM and other conditions in the differential diagnosis (including Mycobacterium tuberculosis) have been excluded (algorithm 1). (See 'Diagnosis' above.)

Differential diagnosis – The differential diagnosis of NTM lymphadenitis includes other infectious causes of unilateral lymphadenitis, benign cysts, and malignancy. A combination of clinical, radiographic, and laboratory findings (including serology and microbiologic testing) may be necessary to distinguish NTM lymphadenitis from these conditions. (See "Cervical lymphadenitis in children: Etiology and clinical manifestations" and "Cervical lymphadenitis in children: Diagnostic approach and initial management".)

Management

For patients with isolated NTM or suspected NTM lymphadenitis in a location with low risk of facial nerve injury (ie, excluding preauricular or intraparotid involvement), we suggest surgical excision without antimycobacterial therapy as the initial intervention (Grade 2B). Antimycobacterial therapy or observation alone are alternatives for children and families who wish to avoid surgery. Excision has higher cure rates, more rapid healing, and better cosmetic results than other interventions. (See 'Surgical excision (preferred)' above.)

For patients with NTM who are not candidates for surgical excision, we suggest antimycobacterial therapy with or without gentle curettage rather than observation alone (Grade 2C). We prefer antimicrobial therapy to observation because the risk of fistula formation is lower. Observation is an alternative for patients and families who are concerned about adverse effects of a prolonged course of antimycobacterial therapy. (See 'Antimycobacterial therapy' above and 'Observation' above.)

-Pending culture results in children for whom M. tuberculosis is not a concern, we usually treat with a macrolide (azithromycin or clarithromycin) in combination with another agent (either a rifamycin or ethambutol) (table 2) given the predominance of MAC. Patients typically are treated until their symptoms resolve (usually three to six months). (See 'Antimycobacterial therapy' above.)

-If M. tuberculosis remains a concern, we treat with at least four drugs (eg, isoniazid, rifampin, ethambutol, and macrolide). (See 'Antimycobacterial therapy' above.)

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Topic 86045 Version 25.0

References

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