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Emergence of Nontuberculous Mycobacterial Lymphadenitis in Children After the Discontinuation of Mandatory Bacillus Calmette and GuÉrin Immunization in France

Lacroix, Adèle, MD*; Piau, Caroline, MD; Lanotte, Philippe, MD, PhD; Carricajo, Anne, MD, PhD§; Guillouzouic, Aurelie, MD; Peuchant, Olivia, MD, PhD; Cady, Anne, MD**; Dupin, Clarisse, MD††; Fangous, Marie-Sarah, MD‡‡; Martin, Christian, MD, PhD§§; Cariou, Marie-Estelle, MD¶¶; Le Gall, Florence, MD‖‖; Bemer, Pascale, MD; Tattevin, Pierre, MD, PhD* on behalf of the MYCOMED Group

The Pediatric Infectious Disease Journal: October 2018 - Volume 37 - Issue 10 - p e257–e260
doi: 10.1097/INF.0000000000001977
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Eighty-five children were diagnosed with culture-confirmed nontuberculous mycobacterial cervical lymphadenitis within the MYCOMED surveillance network from 2004 to 2013. The mean incidence sharply increased from 0.57 to 3.7 per 100,000 children per year, after the discontinuation of mandatory bacillus Calmette and Guérin immunization in 2007. Cases were documented as Mycobacterium avium (62.3%), Mycobacterium intracellulare (15.3%) and Mycobacterium lentiflavum (12.9%). Outcome was favorable in all, with or without surgery or antimycobacterial treatment.

From the *Infectious Diseases

Bacteriology, Pontchaillou University Hospital, Rennes, France

Bacteriology, Bretonneau University Hospital, Tours, France

§Bacteriology, Hôpital Nord University Hospital, Saint-Etienne, France

Bacteriology, Hotel Dieu University Hospital, Nantes, France

Bacteriology, Bordeaux University Hospital, Bordeaux, France

**Microbiology, Bretagne-Atlantique Hospital, Vannes, France

††Microbiology, Yves Le Foll Hospital, St Brieuc, France

‡‡Bacteriology, Brest University Hospital, Brest, France

§§Bacteriology, Dupuytren University Hospital, Limoges, France

¶¶Microbiology, Bretagne Sud Hospital, Lorient, France

‖‖Microbiology, Cornouailles Hospital, Quimper, France.

Accepted for publication November 26, 2017.

The authors have no funding or conflicts of interest to disclose.

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).

Address for correspondence: Pierre Tattevin, MD, PhD, Infectious Diseases and Intensive Care Unit, Pontchaillou University Hospital, 2 Rue Le Guilloux, 35033 Rennes Cedex, France. E-mail: pierre.tattevin@chu-rennes.fr.

Nontuberculous mycobacterial (NTM) lymphadenitis affects mostly young children between the age of 1 and 5 years, with a slight female predominance. Children present with progressive unilateral enlargement of cervical or facial lymph nodes, with no or limited pain, and no fever. During a course of several weeks to months, a deep abscess develops, progressively surrounded by violaceous coloration of skin and finally evolve to spontaneous external fistula (Fig., Supplemental Digital Content 1, http://links.lww.com/INF/D70). Management of NTM lymphadenitis is poorly standardized and remains debated.1

Bacillus Calmette and Guérin (BCG) is a live attenuated vaccine recommended for the prevention of tuberculosis in many countries. The large number of mycobacterial antigens included in BCG vaccine may confer a significant protection against NTM, although the extent of this protection in terms of mycobacterial species, level of protection and duration remains undefined.2 Previous surveillance studies have reported an emergence of NTM lymphadenitis in children after the discontinuation of BCG immunization policies in Sweden3 and Czech Republic.4 We report the emergence of NTM lymphadenitis in children since the discontinuation of routine BCG immunization in France in 2007, with specific focus on patients characteristics, management and outcome.

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MATERIALS AND METHODS

We performed a retrospective study of all children with culture-confirmed NTM lymphadenitis documented in 11 French hospitals within the MYCOMED network from 2004 to 2013. The MYCOMED network was created on a voluntary basis and collects data on all culture-positive mycobacterial infections diagnosed in the participating hospitals. These hospitals serve as referral sites, with a population catchment area estimated at 6 million inhabitants, including 350,000 children less than 5-year-old. Cases were identified through computerized databases or microbiology laboratory registry and were enrolled if they fulfilled the following criteria: (1) age <18 years by the time of lymphadenitis diagnosis and (2) identification of NTM from at least 1 sample originating from lymph node. NTM lymphadenitis was identified from positive cultures by molecular hybridization (HAIN lifesciences test strip; BIOcentric, Bandol, France), with RNAr 16S and/or with heat shock protein hsp65-based polymerase chain reaction and sequencing. Data were collected from medical records on a standardized questionnaire. We used Georgetown classification,5 to categorize NTM lymphadenitis: stage I refers to painless, firm lymphadenitis, adherent to overlying skin; stage II refers to fluctuant lymphadenitis; stage III refers to skin changes with violaceous coloration and thinning and stage IV refers to fistula. Surgery was classified as complete excision, partial excision, incision and drainage, fine-needle aspirations or no surgery.6 Univariate analysis was performed with R software to identify variables associated with therapeutic management and variables associated with complications, using Fischer exact test for categorical variables. This study was approved by the Rennes University Hospital Institutional Review Board.

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RESULTS

During the study period, 85 cases of NTM lymphadenitis were documented in children within our network. A mean of 2 new cases were diagnosed annually from 2004 to 2007, before the discontinuation of mandatory BCG immunization in children, the mean incidence increased to 12.8 new cases each year from 2008 to 2013 (Fig. 1). The mean annual incidence in children less than 5-year-old can be estimated at 0.57 per 100,000 from 2004 to 2007 versus 3.7 per 100,000 from 2008 to 2013 (P = 0.01). Patients characteristics, clinical presentation, microbiology and treatment are presented in Table 1. Antimycobacterial treatment included macrolide monotherapy (n = 28), macrolide–rifampin (n = 12) and macrolide–rifampin–ethambutol (n = 4), for a median duration of 159 days (range, 45–450). The only variable associated with treatment choice was the hospital where children were managed (P < 0.0001), with striking differences from one site to another, in terms of surgery (range, 33%–100%), and antimycobacterial treatment (range, 0%–100%). We found no association between NTM lymphadenitis stage and management (P = 0.282). Of the 85 children enrolled, 56 (65.9%) were cured with no sequel, 22 (25.9%) were lost to follow-up and 7 were still on antimycobacterial treatment at last follow-up. Complications were reported in medical charts during the follow-up for 37 children (43.5%), including fistula (n = 27), unaesthetic scar (n = 5), relapse (n = 4) and abscess (n = 2). Among the 60 children who underwent surgery, 9 (15%) required a second surgical treatment. Univariate analysis found no factor predictive of complication, with similar rates whatever the management strategy.

TABLE 1

TABLE 1

FIGURE 1

FIGURE 1

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DISCUSSION

This multicenter study suggests that NTM lymphadenitis has emerged in children after the discontinuation of mandatory BCG immunization in 2007 in France, with an incidence estimated at 0.57 per 100,000 per year in children younger than 5-year-old within the MYCOMED network during the 4 years when BCG was routinely administered in children, as compared with 3.7 per 100,000 per year during the 6 years that followed discontinuation of mandatory BCG immunization in children. Of note, the latter incidence is similar to those estimated after the discontinuation of mandatory BCG immunization in Sweden3 and Czech Republic4 (respectively, 5.7 and 4.8 per 100,000). The characteristics of these 85 cases are in agreement with previous series in children, including female predominance, and species distribution. Most cases were related to Mycobacterium avium and M. intracellulare.6M. lentiflavum, the third most common species in our study (12.9%), was first described in 1996 and shares similar phenotypic and biochemical properties with M. avium, while genetic characteristics are closer to those of Mycobacterium simiae. Few cases of M. lentiflavum lymphadenitis have been reported,7 although a recent series from Spain reported 17 cases.8 Given that most cases have been identified by RNAr 16S-based polymerase chain reaction and sequencing in the study reported herein, the emergence of NTM lymphadenitis ascribed to M. lentiflavum may merely reflect progress in mycobacterial identification tools, rather than changes in species distribution.

We found that the management of NTM lymphadenitis was highly variable from one site to another within our network. This may be related to the absence of consensus guidelines and the lack of evidence-based data in this field. Incision and drainage were performed in one third of patients in our study (28/85), despite robust data advocating against this surgery. There are few comparative studies on the management of NTM lymphadenitis. A randomized study on 100 children found that complete surgical resection was superior to a combination of clarithromycin and rifampin during 12 weeks, with cure rates of 96% versus 66%, P < 0.001.9 A recent meta-analysis that included data on 1951 children found cure rates of 98% [95% confidence interval (CI): 97.0%–99.5%] for complete excision, 73.1% (95% CI: 49.6%–88.3%) for antimycobacterial antibiotics and 70.4% (95% CI: 49.6%–88.3%) for “no intervention.” Compared with “no intervention,” only complete excision was associated with cure (odds ratio = 33.1; 95% CI: 10.8–102.9; P < 0.001) and shorter healing time. However, complete excision is associated with a 10% risk of facial nerve palsy (2% permanent).6 On the other hand, most cases of NTM lymphadenitis resolve even if left untreated, with or without fistula. The impact of antimycobacterial treatment in either situation (surgical abstention or excision) is difficult to ascertain, because of heterogeneity in treatment regimens, case-mix and limited sample size. However, no study found any benefit in terms of cure rates, and one randomized study found no impact on healing time, with median time to recovery of 40 weeks with antimycobacterial treatment versus 36 weeks with the “wait-and-see” strategy.10 Taking these data into account, some experts elaborated guidelines for the management of NTM lymphadenitis adjusted on clinical situation,6 while American recommendations advocate for complete resection whenever feasible.1 A multicenter randomized controlled trial would be required to move forward in this field.

This study has limitations. First, because of its retrospective, observational, multicenter design, the management of children was not standardized, and a significant proportion of them were lost to follow-up. Second, given the significant changes in diagnostic procedures during the study period, progress in microbiology techniques and better awareness of NTM lymphadenitis among clinicians may have contributed to the increasing number of diagnosis since 2007. Third, the temporal association between the discontinuation of routine BCG immunization in children in France and the emergence of NTM lymphadenitis in this population should not be inferred as causality. However, this study has strengths, as it relied on a multicenter network that was engaged in routine surveillance of NTM diseases 4 years before and 6 years after BCG discontinuation, with repeated quality controls. In addition, this network did not significantly change during the study period in terms of population covered and in terms of diagnostic procedures.

In conclusion, we found a dramatic increase in the incidence of NTM lymphadenitis diagnosed in children within a large network in France after the discontinuation of routine BCG immunization in 2007. These data are in agreement with surveillance data from Sweden3 and Czech Republic,4 as well as with animal models,2 suggesting that the discontinuation of routine BCG vaccine may be followed by the emergence of NTM lymphadenitis in children.

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REFERENCES

1. Griffith DE, Aksamit T, Brown-Elliott BA, et alATS 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.
2. Orme IM, Collins FMProphylactic effect in mice of BCG vaccination against nontuberculous mycobacterial infections. Tubercle. 1985;66:117–120.
3. Romanus V, Hallander HO, Wåhlén P, et alAtypical mycobacteria in extrapulmonary disease among children. Incidence in Sweden from 1969 to 1990, related to changing BCG-vaccination coverage. Tuber Lung Dis. 1995;76:300–310.
4. Trnka L, Danková D, Svandová ESix years’ experience with the discontinuation of BCG vaccination. 4. Protective effect of BCG vaccination against the Mycobacterium avium intracellulare complex. Tuber Lung Dis. 1994;75:348–352.
5. Penn R, Steehler MK, Sokohl A, et alNontuberculous mycobacterial cervicofacial lymphadenitis–a review and proposed classification system. Int J Pediatr Otorhinolaryngol. 2011;75:1599–1603.
6. Zimmermann P, Tebruegge M, Curtis N, et alThe management of non-tuberculous cervicofacial lymphadenitis in children: a systematic review and meta-analysis. J Infect. 2015;71:9–18.
7. Blyth CC, Best EJ, Jones CA, et alNontuberculous mycobacterial infection in children: a prospective national study. Pediatr Infect Dis J. 2009;28:801–805.
8. Jiménez-Montero B, Baquero-Artigao F, Saavedra-Lozano J, et alComparison of Mycobacterium lentiflavum and Mycobacterium avium-intracellulare complex lymphadenitis. Pediatr Infect Dis J. 2014;33:28–34.
9. Lindeboom JA, Kuijper EJ, Bruijnesteijn van Coppenraet ES, et alSurgical excision versus antibiotic treatment for nontuberculous mycobacterial cervicofacial lymphadenitis in children: a multicenter, randomized, controlled trial. Clin Infect Dis. 2007;44:1057–1064.
10. Lindeboom JAConservative wait-and-see therapy versus antibiotic treatment for nontuberculous mycobacterial cervicofacial lymphadenitis in children. Clin Infect Dis. 2011;52:180–184.
Keywords:

nontuberculous mycobacteria; lymphadenitis; children; bacillus Calmette and Guérin immunization

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