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Comparison of treatment modalities for non-tuberculous mycobacterial cervicofacial lymphadenitis in children

T. Mennes V. Vander Poorten F. Vermeulen G. Hens
t. Mennes V. Vander Poorten F. Vermeulen G.母雞

Received: 10 September 2023 / Accepted: 23 November 2023 / Published online: 12 December 2023
(c) The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2023
(c)作者,根據Springer Nature 2023的一部分Springer Verlag GmbH德國的獨家許可

Abstract 摘要

Purpose We aim to compare the different treatment modalities of non-tuberculous cervicofacial lymphadenitis in children, by means of a retrospective study conducted in the University Hospitals of Leuven of patients treated between 2012 and 2022. Methods For this retrospective cohort study, data were collected and pseudonimised from 52 patients with non-tuberculous cervicofacial lymphadenitis, who were treated in our hospital between January 2012 and December 2022, either conservatively, antibiotically, surgically, or with a combination of these options.

We only included patients who were considered immunocompetent. All of the included patients were below 10 years at time of treatment. We collected data regarding time to resolution and adverse effects, i.e., skin discoloration, excessive scar formation, fistula formation, persistence of adenopathies after treatment, need for additional treatment, facial nerve paresis/ paralysis, or systemic side-effects due to antibiotic treatment.

Results The mean time to resolution (in days) when looking at primary treatments, was shortest in partial excisions (16), followed by complete excisions (19), antibiotic therapy (129), incision and drainage (153), curettage (240), and finally conservative management (280). Taking into account isolated treatments (i.e., both primary and adjuvant), we also observed consistently faster time to resolution in surgical and antibiotic treatments when compared to conservative treatment. Antibiotic therapy ( ), incision and drainage ( ) were associated with a significantly higher need for adjuvant treatment. Curettage was associated with a higher incidence of fistula formation and higher number of adjuvant treatments .
結果在初步治療中,部分切除(16例)的平均緩解時間(天)最短,其次是完全切除(19例),抗生素治療(129例),切開引流(153例),刮除術(240例),最後是保守治療(280例)。考慮到孤立的治療(即,主要的和輔助的),我們還觀察到與保守治療相比,手術和抗生素治療的消退時間更快。抗生素治療( )、切開引流( )與輔助治療需求顯著增加相關。刮除術與瘺管形成的發生率較高相關 和輔助治療次數較多

Conclusions This study shows a faster resolution of nontuberculous mycobacterial cervicofacial lymphadenitis in children when treated surgically, more specifically when treated with partial or complete lymph node excision. Antibiotic treatment also leads to faster resolution than conservative management. There was a low rate of complications, and no permanent facial nerve damage was reported.

Keywords Treatment Nontuberculous mycobacteria Cervicofacial lymphadenitis Paediatrics
關鍵詞治療 非結核分枝桿菌 頸面部淋巴結炎 兒科

Introduction 居間

The distinct clinical presentation of cervicofacial lymphadenitis caused by tuberculous pathogens was already well known in the Middle Ages under the name of Scrofula. Historically, the causative pathogen was almost always tuberculous in origin, yet starting from the 2nd half of the twentieth
century, nontuberculous mycobacteria (NTM) have been reported more and more as being the causative agents [1].
Nontuberculous mycobacteria (NTM) are bacteria found ubiquitously in the environment, for example, in soil, domestic and wild animals, as well as food and water sources. They are a separate division of the genus Mycobacterium (including M. tuberculosis and M. leprae). The genus comprises more than 172 species, even though only a fraction of these have been determined to be pathogenic [2]. Cervicofacial lymphadenitis in otherwise healthy children is the most frequent clinical syndrome caused by NTM, other possibilities are skin and soft tissue infections, pulmonary disease (mostly occurring in individuals with pulmonary

comorbidities) or disseminated disease (mostly occurring in immunocompromised patients) [3].
NTM cervicofacial lymphadenitis is characterized by a more indolent course than a pyogenic bacterial lymphadenitis. Slowly enlarging nontender lymph nodes will undergo liquefaction and abscess formation. Typically, there is skin involvement, with a violaceous color of the overlying skin and eventually rupture with fistula formation. Cervicofacial lymphadenitis (CL) caused by NTM is usually not complicated by systemic symptoms/disease, in contrast to tuberculous lymphadenitis [4].
The condition is self-limiting, albeit with a prolonged healing process and a risk of a poor esthetic outcome. Besides observation only, treatment options include antibiotic therapy or surgical incision/curettage or excision of the affected nodes.
In this study, we retrospectively review the treatment modalities used, adverse effects and outcomes in patients with NTM CL, to determine the treatment modality associated with the lowest average time to resolution in our clinic, taking into account the incidence of complications.
在這項研究中,我們回顧性審查了NTM CL患者的治療方式、不良反應和結局,以確定我們診所中與最短平均緩解時間相關的治療方式,同時考慮併發症的發生率。
Based on our clinical observations and literature data, our hypothesis is that total excision of affected lymph nodes may result in the shortest time to resolution, followed by partial excision, curettage, incision and drainage, antibiotic management and then conservative management. Furthermore, we hypothesise that antibiotic treatment in monotherapy may not be superior to observation without intervention. Finally, we hypothesise that total lymph node excision may have the highest amount of permanent undesired effects, i.e., nerve paresis/paralysis.

Methods 方法

Study design 研究設計

This study aims to retrospectively assess the outcomes and complications of the different management strategies for NTM CL in children that were applied in our hospital between January 2012 and December 2022.
本研究旨在回顧性評估2012年1月至2022年12月期間在我院應用的兒童NTM CL不同管理策略的結局和併發症。
Patient characteristics (gender and age at presentation) and infection characteristics (anatomical subsite, responsible organism, method of diagnosis) were noted.
Treatment strategies were divided in a surgical, a medical, and a conservative group. Surgical treatments include complete excision, partial excision, incision and drainage, and finally curettage. In our study, we defined partial excision as surgical removal of a part (of unspecified size) of one lymph node, or removal of one lymph node, where others are left behind, due to the fact that the surgeon deemed it unsafe to remove more. Medical treatments comprised of clarithromycin, azithromycin, ciproxin, rifampicin, rifambutin, or a combination of these antibiotics. The conservative group only contains patients in whom no active treatment was initiated.
For each primary treatment strategy, the time to resolution was analysed, as well as the need for adjuvant treatment. By time to resolution, we mean the time period between onset of symptoms and documentation of closed skin (where applicable) or documentation of resolution of clinically detectable adenopathies (where no skin rupture nor incision was applicable). Since the majority of our patients underwent multiple treatments, we also separately analysed the outcomes of the individual treatments combined (meaning all of the patients undergoing the same treatment whether as primary or as adjuvant treatment), using the adjusted time to resolution. By adjusted time to resolution, we refer to the time from initiation of (secondary) treatment until documented resolution.
Finally, the adverse effects were analysed, for the immediately surgically treated group on one hand, the primarily antibiotically treated group on the other, and finally a disease induced group.
The Ethical Committee of KU Leuven granted favorable advice to conduct this study (reference number: S67584). We used the STROBE cohort checklist when writing our report .
KU Leuven倫理委員會同意進行本研究(參考編號:S67584)。我們在撰寫報告 時使用了STROBE隊列檢查表。

Participants 參與者

We included all patients that were treated in the University Hospitals of Leuven between January 2012 and December 2022 for NTM CL. All data were collected and processed in 2023.
我們納入了2012年1月至2022年12月期間在魯汶大學醫院接受NTM CL治療的所有患者。所有數據均於二零二三年收集及處理。
To identify and include patients, we used the operation theatre program on one hand, and lists of patients who received IGRA (Interferon-Gamma Release Assays) testing, Mantoux testing, and Bartonella serology testing on the other, which are all part of the standard work-up of children with chronic cervical lymphadenitis. We were provided these lists through the laboratory.
Patients were included if years, with cervical lymphadenitis based on NTM as proven by culture or PCR (both of these tests were always asked for upfront), or with a suggestive clinical presentation, a positive Mantoux test and a negative IGRA. In this scenario, necrotizing granulomatous inflammation was always seen on pathology, yet only one was positive for mycobacteria on Ziehl-Neelsen staining. We had sufficient material for analysis in all cases.
如果患者年齡為 歲,根據培養或PCR(這兩種檢測總是要求預先進行)證實的NTM,患有頸部淋巴結炎,或具有提示性臨床表現、Mantoux檢測陽性和IGRA陰性,則納入研究。在這種情況下,壞死性肉芽腫性炎症總是在病理學上看到,但只有一個是陽性的分枝桿菌的Ziehl-Neelsen染色。我們有足夠的材料來分析所有的情況。
We set out to exclude children with known primary or secondary immunodeficiency. This turned out to be one child, who turned out to have an IL-12/IFN-g axis defect.
We also set out to exclude children in whom not a single diagnostic method proved positive, though the clinical course was highly suggestive of an NTM infection. No

patients were excluded because of age . This also turned out to be one child.
患者因年齡 而被排除。這也是一個孩子。
In total, we were able to include 52 children.
Follow-up of these patients was performed in ambulatory care, either through the ENT-HNS department, the paediatric department or both.
All of the variables of interest were extracted from the central UZ Leuven electronic medical record system.
所有感興趣的變量都是從中央UZ Leuven電子病歷系統中提取的。
To comply with privacy regulations, we used pseudonymisation of data. The data were reviewed by a researcher not directly involved in the care of the patients to avoid bias.

Statistical analysis and methods

We used IBM SPSS 28.0 (SPSS Inc. Chicago, IL) for statistical analysis. Database collection was performed using Microsoft Excel (2013).
我們使用IBM SPSS 28.0(SPSS Inc.芝加哥,IL)進行統計分析。使用Microsoft Excel(2013)進行資料庫收集。
Chi-square and Fischer exact tests were used to compare anatomic location and primary treatment choices, as well as to compare all treatments and the different parameters regarding adjuvant treatment and adverse effects.
Mann-Whitney tests were used to compare mean time to diagnosis and follow-up as well as time to resolution with regard to treatment variables, after assessing normality through the Shapiro-Wilk test. (None of the continuous outcome parameters was normally distributed).
通過Shapiro-Wilk檢驗評估正態性後,使用Mann-Whitney 檢驗比較治療變量的平均診斷和隨訪時間以及消退時間。(None連續結果參數的正態分布)。
Checking for confounders was performed with multiple linear regression and logistic regression.
Two-sided values of less than 0.05 were considered significant.
認為雙側 值小於0.05具有顯著性。

Results 結果

Participants 參與者

Three patients were lost to follow-up before complete resolution of all adenopathies was observed. Two of those three were seen again in our department for unrelated reasons 2 years later, where we documented clinical resolution of adenopathies.
Patient characteristics are summarised in Table 1.
Table 1 Patient characteristics
Age at presentation  就診時的年齡
We observed a male proportion (gender ratio) of 0.29 . The mean age of the patients was 3 years and 4 months, range ( 7 months to 9 years and 4 months).
我們觀察到男性比例(性別比)為0.29。年齡7個月~ 9歲4個月,平均3歲4個月。

Infection characteristics

Infection characteristics are summarized in Table 2. In of patients, diagnosis was confirmed by culture and/ or PCR. In the other of cases, culture and PCR were negative, but the clinical presentation in combination with a positive Mantoux test and negative IGRA test sufficed to make the diagnosis.
感染特徵總結見表2。在 例患者中,通過培養和/或PCR確認了診斷。在其他 例病例中,培養和PCR均為陰性,但臨床表現結合陽性Mantoux試驗和陰性IGRA試驗足以做出診斷。
In our series, of positive cultures and/or PCR's reported Mycobacterium avium as the responsible organism. Mycobacterium malmoense, interiectum and kansasii were isolated only once, respectively. In the patient, where M. kansasii was detected, IGRA was positive. This was
Table 2 Infection characteristics
Method of diagnosis  診斷方法
Necrotizing granulomatous inflammation on pathol- 24 (46.2%) ogy in combination with positive tuberculin test with negative IGRA
Culture/PCR 培養/PCR
Responsible organism  責任微生物
Mycobacterium avium 鳥分枝桿菌
Mycobacterium malmoense 馬爾默分枝桿菌
Mycobacterium interiectum
Mycobacterium kansasii 堪薩斯分枝桿菌
Clinical presentation
Painless swelling 不痛的腫大
Tender swelling 壓痛腫脹
Fistula formation 瘺管形成
Indurated Skin 硬化皮膚
Violaceous Skin 紫色皮膚
Anatomical location  解剖位置
Submandibular (level Ib)
Parotid 腮腺
Submental (level Ia) 頦下(Ia級)
Cervical (levels II-III)
Retropharyngeal 咽後
coincidentally the only patient who did not receive any surgical interventions throughout the entire follow-up.
Local symptoms at presentation were documented, as well as anatomical location of the lesions. The clinical presentation tended to include multiple symptoms per patient.
Mean time to presentation was 40.13 days, with a range between 0 and 987 days.
至就診的平均時間為40.13天,範圍為0 - 987天。

Outcome of primary treatment

The primary treatments are documented in Table 3.
We note that of all our patients were given regular antibiotics (amoxicillin, amoxicillin/clavulanic acid or a short course of clarithromycin or azithromycin) before other therapeutic options were considered. This was always done because of an initial diagnostic uncertainty (i.e., suspicion of a pyogenic bacterial lymphadenitis), and were always given short term ( weeks). Whenever we talk about antibiotic use from this point on, we are referring to mycobacterialspecific treatments which were given long term and which are documented in Table 3.
我們注意到,在考慮其他治療選擇之前,我們所有患者中有0#例接受了常規抗生素治療(阿莫西林、阿莫西林/克拉維酸或短期克拉黴素或阿奇黴素)。由於初始診斷的不確定性(即,懷疑化膿性細菌性淋巴結炎),並且總是給予短期( 周)。從這一點開始,每當我們談論抗生素的使用時,我們指的是長期給予的分枝桿菌特異性治療,並在表3中記錄。
There was an average delay to treatment of 28 days, counting from the day to presentation.
Patients were treated conservatively in 3 out of 12 cases against the preference of the attending physicians because of explicit request by the parents.
Dosage of antibiotics was standardised, namely, day for rifabutin, day for ethambutol, day for rifampicin, twice daily for clarithromycin, and day for azithromycin.
Mean time of follow-up was 297.50 days with a range between 54 and 1094 days.
平均隨訪時間為297.50天,範圍為54 - 1094天。
Table 3 Primary treatment characteristics
Rifabutin + azithromycin
Rifabutin + clarithromycin
Rifampicin + azithromycin
Rifampicin + clarithromycin
Duration of antibiotic treatment
Mean (days) 119.78
Range (days)
Incision and drainage 切開引流
Partial excision 部分切除
Complete excision 完整切除
Conservative management 保守治療
Percentages are expressed in function of total population

Table 4 shows outcome characteristics of primary treatments.
To compare effectiveness of the different primary treatments, we defined time to resolution as the time between the date of first treatment (start of antibiotics or operation date) and first documentation of (clinical) resolution of adenopathies and skin closure (if skin opening was relevant, either due to fistula formation or surgical procedure). For this analysis, we only took into account the first treatment given, though the majority of our patients underwent secondary treatments during the time to resolution. We compared time to resolution within the treatment groups to time to resolution in the conservatively managed group, not to the study mean.
The mean time to resolution was 153 days (range 6-904 days) (Table 4). As shown, time to resolution was significantly shorter (compared to conservative management) in all of the treatment groups.
We also observed significant differences in the need for adjuvant therapies. In all patients receiving antibiotics, incision and drainage or curettage, and in 11/12 patients receiving conservative treatment as a first treatment choice, adjuvant (surgical or antibiotic or both) treatment was performed, in contrast to of patients and 0/12 patients undergoing partial or complete excision, respectively.
Reasons for adjuvant therapy are given in Table 4 and more succinctly in Table 5. Curettage as primary therapy was associated with a significant higher risk of fistula development.
Number of adjuvant therapies are detailed in Table 4 and ranged between 0 and 3. A significantly higher number of additional procedures were seen after curettage, and relatively fewer after antibiotics or conservative management as primary treatment. The types of adjuvant therapies used are shown in Table 5.
輔助治療的數量詳見表4,範圍為0 - 3。刮宮術後的額外手術數量明顯增加,而抗生素或保守治療作為主要治療後的額外手術數量相對較少。使用的輔助治療類型見表5。
No correlation was found between patient characteristics (age, gender) or location of the infection with time to resolution or number of adjuvant procedures.

Outcome of isolated treatment

Since 36/52 patients underwent more than one treatment, we also evaluated the effectiveness of the isolated treatment options, i.e., both as primary or secondary treatment choice.
Adjusted time to resolution, as a function of the different isolated treatment modalities, is shown in Table 6. By adjusted, we mean that for both the primary and adjuvant treatments the time period between time of symptom onset and start of treatment is subtracted. For the conservative management, we adjusted for time to presentation to compare the different modalities.
Table 5 Adjuvant treatments
Need for adjuvant treatment
Number of adjuvant treatments
Adjuvant treatments  輔助治療
Azithromycin + rifampicin
Clarithromycin + rifampicin
Clarithromycin + rifabutin
Azithromycin + rifabutin
Azithromycin + ethambutol
Incision and drainage 切開引流
Partial excision 部分切除
Complete excision 完整切除
Reason for adjuvant treatment
Skin problems 皮膚問題
Persistent adenopathy 持續性淋巴結病
amount of patients needing adjuvant treatment, because this is a multiple response variable. The number of patients needing adjuvant treatments is listed above
amount of patients needing adjuvant treatment, because this is a multiple response variable. of patients needing adjuvant treatment (18) did so because of multiple reasons
需要輔助治療的患者數量,因為這是一個多應答變量。 例需要輔助治療的患者(18例)因多種原因而接受輔助治療
Table 6 Adjusted time to resolution following isolated treatment options
Mean Standard deviation 標準偏差 value
Antibiotic therapy 抗生素治療 152.78 107,882
Incision + drainage 切開+引流 155.9 125,046
Curettage 233.75 143,993
Partial Excision 部分切除 13.75 6,31
Complete Excision 完整切除 22.25 19,522
Conservative management
281.4 265.5 NA
These values for conservative management are the same as in Table 4, because conservative management was never used as an adjuvant treatment
We compared the different treatment modalities, not to the mean of the study population but to the mean of those (initially) treated conservatively.
Results are shown in Table 6 . The values in this table refer to a comparison with conservative management (as before), not with the mean study population. When making this comparison, all of the isolated treatments were associated with a significantly shorter time to resolution, as well as curettage.
結果示於表6中。本表中的 值是指與保守治療(如前所述)的比較,而不是與平均研究人群的比較。當進行這種比較時,所有單獨治療與顯著更短的消退時間以及刮除術相關。

Complications 併發症

Complications are shown in Table 7.
We divided them into a surgically induced group, an antibiotically induced group, and a disease induced group. None of the primary treatments were significantly associated with a specific complication. No associations were found between any of the complications and patient, infection or treatment characteristics.
None of the patients included in this study suffered a facial nerve (branch) paralysis, nor permanent paresis. Despite the use of the nerve integrity monitor in all patients, four facial nerve pareses were observed, three of which after a complete lymph node excision, one after a curettage. All of them recovered completely.
One postoperative bleeding was observed, in a complete lymph node excision as adjuvant therapy.
Three postoperative abscess formations were observed, two of which in complete lymph node excisions, one in a partial lymph node excision. All three of them required drainage.
Of the patients treated with antibiotics, none were reported to have suffered neutropenia, uveitis, or other antibiotic side effects. Gastro-intestinal symptoms through antibiotic therapy occurred twice, both in patients taking azithromycin in combination with rifabutin.
Skin discoloration (seen as a purple hue which did or did not persist for a long period of time) was reported in some patients after documented resolution of clinically detectable adenopathies. Since the documentation on the final status of the scar was not supported with pictures added to the patient file and since both their documentation and the decision to provide additional therapies in this regard (i.e., silicone gel and/or lasering, corticoid injections,...) might sometimes have been a parental incentive rather than a medical one, we opted not to subject the parameters skin discoloration and excessive scar formation to further statistical analysis.
None of the patients included in this study had a persistent fistula at the end of treatment/follow-up.
Table 7 Complications 表7併發症
Facial nerve paresis 面神經麻痹
Postoperative bleeding 術後出血
Abscess Formation after surgery
Antibiotically induced
GI symptoms
Disease induced  疾病誘發
Skin discoloration 皮膚變色
Excessive scar formation

Discussion 討論

The primary goal of our study was to map treatment of NTM cervicofacial lymphadenitis and its relation to time to resolution of the infection on one hand, and adverse events on the other.
We had to focus mostly on primary treatments, i.e., the initial treatments given to the patients before switching to adjuvant therapy. We make this remark, because we only had one patient in total who solely underwent conservative management and had resolution of the infection without intervention. Furthermore, we had zero patients who received antibiotic therapy as a primary therapy without receiving adjuvant (surgical) therapy afterwards.
We opted to make the distinction between time to resolution with respect to the entire disease course on one hand, and adjusted time to resolution, where we isolated the different treatment modalities and looked at average time to achieve resolution from start of treatment to detection of intact skin without clinically detectable adenopathies.
Our first hypothesis was that total excision of affected nodes would result in the shortest time to resolution, followed by partial excision, curettage, incision and drainage, antibiotic management and then conservative management, based on the extensive meta-analysis by Zimmerman et al
根據齊默爾曼等 的廣泛薈萃分析,我們的第一個假設是受影響淋巴結的全切除將導致最短的緩解時間,其次是部分切除、刮除、切開引流、抗生素治療,然後是保守治療。
Zimmerman et al. did not report time to resolution, yet they investigated cure rates, which inversely relates to our 'need for adjuvant treatment'.
They reported adjusted mean cure rates of for a complete excision, where we saw a adjuvant treatment, a for partial excision, where we saw a need for adjuvant treatment, for a curettage, where we saw a need for adjuvant treatment, for incision and drainage, where we saw need for adjuvant treatment, for antibiotics, where we saw a need for adjuvant treatment, and for conservative management, where we saw a need for adjuvant treatment. These numbers seem to be comparable for complete excisions and in part for partial excisions (even though Zimmerman makes the remark that statistical results have to be scrutinised because of low total patients who received this treatment-which is also the case in our study), yet do not seem to seem comparable for curettage, incision and drainage, antibiotics and conservative management, where we saw an elevated need for adjuvant treatment. The values of their respective cure rates were not significant, in all cases except for complete excision, where their results most closely match ours.
他們報告的調整後的平均治癒率為:完全切除0#,輔助治療1#,部分切除2#,輔助治療3#,刮宮4#,輔助治療5#,切開引流6#,輔助治療7#,抗生素8#,其中我們看到 需要輔助治療, 需要保守治療,其中我們看到 需要輔助治療。完全切除和部分切除的病例數似乎相當(儘管齊默爾曼指出,由於接受該治療的患者總數較低,因此必須仔細檢查統計結果—我們的研究也是如此),但刮除術、切開引流、抗生素和保守治療的病例數似乎不具有可比性,我們發現這些病例對輔助治療的需求增加。 在所有情況下,除完全切除外,其各自治癒率的 值均不顯著,其中其結果與我們的結果最接近。
In our series, we saw slightly shorter times to resolution with partial excisions than complete excisions. The difference between them was not statistically significant (significance was only achieved comparing them to those treated initially when looking at isolated treatments, or comparing them to the study mean when comparing them to primary treatments). The slight difference might (but is not proven to) be attributable to the fact that either smaller incisions were used, or the first follow-up consultation was planned later on to not risk any dehiscence upon removing the sutures.
Our second hypothesis was that antibiotic treatment may not be superior to conservative management. We now refute this hypothesis in our study population, because we noticed a significantly slower time to resolution when patients were (initially) treated conservatively than when they were (initially) treated antibiotically. In both treatment groups, however, all patients except for one in the conservative group needed adjuvant treatments. A study by Lindeboom et al. showed no significant differences in healing time between conservative management and antibiotic therapy through a combination of clarithromycin and rifabutin [7]. They showed a median time to resolution of 252 days, and 280 days for antibiotics and conservative management, respectively. We observed a mean of 130 days for antibiotics, and 280 days for conservative management. This could also reflect treatment preferences by the parents and/or clinician, where patients choosing the conservative treatment were also more reluctant to eventually undergo surgery, hoping for spontaneous resolution.
我們的第二個假設是抗生素治療可能並不上級於保守治療。我們現在在我們的研究人群中反駁了這一假設,因為我們注意到當患者(最初)接受保守治療時,緩解時間明顯比(最初)接受藥物治療時要慢。然而,在兩個治療組中,除保守組中的一名患者外,所有患者都需要輔助治療。Lindeboom等人的一項研究顯示,保守治療與克拉黴素和利福布雷定聯合抗生素治療之間的癒合時間無顯著差異[7]。他們顯示,抗生素和保守治療的中位緩解時間分別為252天和280天。我們觀察到抗生素治療的平均時間為130天,保守治療的平均時間為280天。 這也可能反映了父母和/或臨床醫生的治療偏好,其中選擇保守治療的患者也更不願意最終接受手術,希望自發解決。
In short, our data does not corroborate theirs, yet almost all of our conservatively managed patients were operated upon or treated antibiotically in a later stage, without an obvious significant link with fistula formation. Our antibiotically treated patients also received adjuvant treatment in all cases, so we cannot claim a shorter time to resolution for antibiotic therapy in monotherapy. We can, however, argue that antibiotics could be a good neo-adjuvant treatment for a more definitive surgical solution as compared to conservative management.
A recent study by Lyly et al. with 52 patients showed that conservative management is a good alternative to surgery [8]. The authors did not take time to resolution of the infection into account, and focused solely on fistula formation. Our data corroborates these data regarding complication rate (we also showed that curettage leads to more fistula formation than conservative management), yet we did show a significant decrease in time to resolution in all of the surgical treatments. As mentioned before, we only had one patient who underwent conservative management without adjuvant treatment.
Our last hypothesis was that complete lymph node excision has the highest amount of permanent adverse effects, i.e., facial nerve paresis or paralysis. For a complete excision, Zimmerman et al. describe a facial palsy rate,
我們的最後一個假設是,完全淋巴結切除具有最高量的永久性不良反應,即,面神經麻痹或癱瘓。對於完全切除,齊默爾曼等人描述了 面癱率,

and wound dehiscence. They describe only fistula formation as opposed to fistula formation in partial excisions. [6] We observed no fistula formation in complete lymph node excision, nor in partial excision. In any case, we observed fewer, and always temporary, facial nerve palsies and only of the marginal mandibular branch after excision of the facial lymph node. In our study, no single treatment modality was significantly associated with the occurrence of any adverse event.
傷口裂開。他們僅描述了 瘺管形成,而不是部分切除中的 瘺管形成。[6]我們觀察到在完全淋巴結切除或部分切除中均無瘺形成。在任何情況下,我們觀察到較少的,總是暫時的,面神經麻痹 和只有邊緣下頜分支切除後,面部淋巴結。在我們的研究中,沒有單一的治療方式與任何不良事件的發生顯著相關。
In treating (suspected) NTM cervicofacial lymphadenitis, the risk of facial nerve damage needs to be balanced against the protracted clinical course after conservative or medical treatment for each individual patient. This requires a multidisciplinary cooperation between the paediatric and ENT-HNS department. The absence of permanent damage in our series reflects that a prudent pre-operative evaluation and surgical technique with facial nerve monitoring could avoid permanent complications.
In UZ Leuven, we have adopted a 'prudent aggressive strategy', where we opt for a complete excision of the affected lymph node(s) when the location does not pose a significant risk for facial nerve damage. In case of suspected proximity to facial nerve branches, we opt for a conservative management when the node is not too large or the skin not too inflamed, or for antibiotic therapy in the assumption that this will make a safe operation more feasible by reducing inflammation in and around the affected node(s). When an abscess forms in the vicinity of the facial nerve, we opt for curettage when possible. We opt for incision and drainage mostly in case of suspicion of classic neck abscess or when a sizeable abscess has formed. Partial excision is mostly used when there are multiple affected lymph nodes or when there is suspected proximity to facial nerve branches. In all of these cases, NIM is used to minimise the risk of facial nerve damage, especially when the facial lymph nodes are involved.
在UZ Leuven,我們採取了「謹慎的積極策略」,當受影響的淋巴結位置不會對面神經損傷構成重大風險時,我們選擇完全切除。在懷疑接近面神經分支的情況下,我們選擇保守治療,當節點不是太大或皮膚不是太發炎時,或者抗生素治療,假設這將通過減少受影響節點及其周圍的炎症使安全手術更加可行。當膿腫在面神經附近形成時,我們儘可能選擇刮宮。我們選擇切開引流主要是在懷疑典型的頸部膿腫或當一個相當大的膿腫已經形成。部分切除術主要用於當有多個受影響的淋巴結或當有懷疑接近面神經分支。 在所有這些情況下,NIM用於最大限度地減少面部神經損傷的風險,特別是當涉及面部淋巴結時。
The data obtained through this study confirms that this is a paradigm which we can keep utilising, aiming at the shortest time to resolution possible while prioritising facial nerve integrity.
Another type of permanent adverse effect is skin discoloration and/or excessive scar formation. These occurred in and of our patients, respectively. A recent article by Willemse et al. showed that the long-term aesthetic outcome of surgical treatment was superior to non-surgical treatment [9]. We could not show a significant difference between the different types of treatment modalities in relation to these (aesthetic) complications. It should be noted that Willemse et al. included almost double our amount of patients, that their patients were on average significantly older at presentation, and that their mean follow-up time was 15.24 years, whereas our mean follow-up time was only 290 days. Three of our patients had adjuvant dermatological treatment (either sequential injection of corticosteroids or laser therapy) for aesthetic reasons, yet almost all of the patients who had these outcomes, were discharged from follow-up because of resolution of the infection and no further aesthetic grievances.
另一種類型的永久性不良反應是皮膚變色和/或過度疤痕形成。這些分別發生在我們的 患者中。Willemse等人最近發表的一篇文章表明,手術治療的長期美學結局優於非手術治療[9]。我們無法證明不同類型的治療方式在這些(美學)併發症方面存在顯著差異。值得注意的是,Willemse等人納入的患者數量幾乎是我們的兩倍,他們的患者平均年齡明顯更大,平均隨訪時間為15.24年,而我們的平均隨訪時間僅為290天。 我們的3名患者因美容原因接受了輔助皮膚病治療(序貫注射皮質類固醇或雷射治療),但幾乎所有具有這些結局的患者均因感染消退而出院,並且沒有進一步的美容不滿。
We need to remark that the different locations (submandibular, parotid, submental, cervical, retropharyngeal) depict the broad location as assessed by the clinician. There was no consistent imaging to map the exact location and, therefore, the exact relation the facial nerve. We found no studies relating the exact location to the number of facial nerve complications. Naturally a parotid location would imply a higher risk yet we could not show this to be true in our study population. We could not show a bias in treatment paradigm either, i.e., the described location was not significantly associated with different primary treatments. A possible explanation for this counterintuitive finding is the fact that the location of the actual adenopathy can still vary quite a lot within the broad "parotid region".
Of the 52 patients included in our study, we were only able to demonstrate with certitude the presence of atypical mycobacteria, either through PCR or through culture, in of our cases. The other patients were included because of suggestive clinical course and necrotizing granulomatous inflammation on pathology, as well as a positive Mantoux test in combination with negative IGRA. Given that only one patient in our series was managed conservatively (and this patient had a positive diagnosis through culture because of spontaneous fistula formation with swabbing of pus), this is rather low, because we were able to collect a decent amount of material for investigation in all of our patients. Similar values can be found in literature, however, for example, as described by Willems et al. [10] Willemse et al. described a sensitivity of of cultures, and of PCR. In our centre, bacteriological culture was always ordered, yet mostly in the earlier years, PCR was sometimes omitted. We do not routinely obtain fine needle aspirations for cultures to avoid fistulisation, and because this rarely change management.
在我們研究的52例患者中,我們僅在0#例病例中通過PCR或培養證實了非典型分枝桿菌的存在。其他患者由於提示臨床病程和病理學上的壞死性肉芽腫性炎症,以及Mantoux試驗陽性與IGRA陰性相結合而被納入。考慮到我們的系列中只有1例患者接受了保守治療(該患者由於自發性瘺管形成伴膿液拭子而通過培養得到陽性診斷),因此 相當低,因為我們能夠在所有患者中收集大量材料進行研究。然而,在文獻中可以找到類似的值,例如,如Willems等人[10]所述,Willemse等人描述的培養物的靈敏度為 ,PCR的靈敏度為 。在我們的中心,細菌培養總是有序的,但大多數在早期,PCR有時被省略。 我們通常不使用細針穿刺進行培養以避免瘺管形成,因為這很少改變治療。
We would like to note that positive IGRA testing is often used to distinguish between tuberculous and nontuberculous lymphadenitis. However, IGRA are most useful in case of mycobacterium avium. We observed one case of mycobacterium kansasii, where IGRA was positive, thus leading to an initial suspicion of tuberculous lymphadenitis. It is known, however, that IGRA is more likely to cause a false-positive reaction in NTM other than mycobacterium avium [11].
This study has some important limitations. First and foremost, this was a retrospective study, including only 52 patients. Randomization was, therefore, not an option. Another important limitation is the absence of a control group, i.e., a group of truly (fully) conservatively managed patients who were not just managed conservatively before

switching to another therapy. A completely conservative approach is advocated by others and also results in complete resolution. Finally, treatment choice is guided by the clinical presentation patient and physician preferences. This will inevitably induce a bias, with more severe or extended disease being treated conservatively until surgery is considered a safe option, resulting in longer time to resolution.

Conclusion 結論

In children with nontuberculous mycobacterial cervicofacial lymphadenitis, the time to resolution is shortest after primary therapy with partial or complete excision, followed by antibiotic therapy, incision and drainage, curettage, and finally conservative management. Complete and partial excision were the only therapies, where further adjuvant treatments could be avoided in the majority of cases. No patient suffered permanent facial nerve damage in our study cohort.
Surgical lymph node excision, therefore, seems the treatment of choice to reduce time to resolution in patients with NTM cervicofacial lymphadenitis in cases, where surgery can be performed without significant risk for facial nerve damage. However, the risk of facial nerve damage needs to be evaluated in individual patients and facial nerve integrity should be prioritised in this ultimately self-limiting disease.
Further research is needed to evaluate the impact of antibiotic therapy, as well as the need for a true complete excision as opposed to partial excision to obtain faster time to resolution.
Funding No funding was obtained for this study.

Declarations 聲明

Conflict of interest The authors have no conflicts of interest.
Ethical approval Compliance with ethical standards was maintained. The Ethical Committee of KU Leuven granted favorable advice to conduct this study (Reference number: S67584). No studies with human participants or animals were performed by any of the authors.
倫理批准保持了對倫理標準的遵守。KU Leuven倫理委員會同意進行本研究(參考編號:S67584)。任何作者都沒有對人類參與者或動物進行研究。

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  1. T. Mennes  T.我的
    tillomennes gmail.com
    1 UZ Leuven, Department of Otorhinolaryngology and Head and Neck Surgery, Leuven, Belgium
    1 UZ Leuven,比利時魯汶耳鼻咽喉頭頸外科
    2 UZ Leuven, Department of Paediatrics, Leuven, Belgium
    2 UZ Leuven,比利時魯汶兒科部
  2. We note that only the most reliable way of diagnosis was withheld for reporting the method of diagnosis, i.e., this does not mean, for example, that those diagnoses which are reported here as been made with culture and/or PCR did not have necrotizing granulomatous inflammation on pathology
    Total percentage , because this is a multiple response variable
    總百分比 ,因為這是一個多響應變量
    (31) of patients had multiple symptoms
    Total percentage , because this is a multiple response variable. (11) of patients had multiple locations. 2 patients had bilateral lymphadenopathies. Both of them had submandibular, parotid and submental adenopathies as well
    總百分比 ,因為這是一個多響應變量。 (11)例患者有多個部位。2例患者有雙側淋巴結病變。他們都有下頜下,腮腺和頦下腺病以及