Cervical lymphadenitis in children: the role of Mycobacterium avium-intracellulare

I

1

Cervical lymphadenitis in children: the role of Mycobacterium avium-intracellulare M. S. Falworth,

M. T. Simpson

Department of’Musillqf~cia1

Surgery, Bedford General Hospital, Bedford, UK

SUMMAR Y. Non-tuberculous mycobacteria are the most frequent cause of mycobacterial cervical lymphadenitis in children. Although uncommon, the incidence in recent years has shown a marked increase. Its early differentiation from tuberculous mycobacterial lymphadenitis is essential as the treatment of choice is early surgical excision rather than antituberculous chemotherapy. Three such cases are reported with emphasis on the differential diagnosis and management.

INTRODUCTION

response to chemotherapy and 8 weeks following the biopsy an open wound with associatedexophytic granulation tissue and intermittent discharge remained. Ten weeks after the initial biopsy, culture confirmed the presence of MA1 which demonstrated multiple resistance to in vitro sensitivity testing. In spite of this report the swelling had partially resolved leaving only some underlying lymphadenopathy and hence the antituberculous chemotherapy was continued for a total of 9 months. At the end of this period total resolution had occurred leaving only a scar from the initial drainage incision.

Diseases caused by non-tuberculous mycobacteria have become increasingly apparent.im3 Of these atypical mycobacteria, Mycobacterium avium-intracellulure (MAI), is the most common cause of infection4 and may present as pulmonary disease, disseminated infection in immunocompromised patients and as a benign cervicofacial, axillary or inguinal’ lymchildren. phadenopathy in Non-tuberculous mycobacterial infections demonstrate multi-drug resistance and hence early and effective surgical intervention is the treatment of choice. Unlike tuberculosis, diseases due to these organisms do not have to be reported to public health laboratories and hence their true incidence may not be fully appreciated although this may be enhanced by increasing the awareness of the disease and by the use of improved investigative techniques.

Case 2 A 4-year-old boy was referred with a 5-week history of a tender, erythematous, lump measuring 2 cm in diameter within the soft tissuesoverlying the left side of the mandible. It had proved to be unresponsive to both penicillin V and Augmentin and later became fluctuant. On examination no cause for the swelling could be elicited. His FBC was normal and the ESR slightly raised at 24mm/h. His chest radiograph was clear and systems enquiry showed nothing untoward. The fluctuant mass was incised and drained and an incisional biopsy performed. A drain was left in the wound and a course of flucloxacillin prescribed. Histopathological examination identified an epithelioid cell granulomatous reaction with Langhan’s giant cells. No acid fast bacilli were found and there was no growth from the culture swab. Triple therapy of rifampicin, pyrazinamide and isoniazid was prescribed. Ten weeks after his presentation indurated nodes persisted and he returned to theatre for further drainage and currettage as excision might have jeopardised the marginal mandibular nerve (Fig. 1). After 11 weeks of culture the presence of MAI was confirmed. Sensitivity screens reported that the mycobacterium was resistant to the antituberculous regimen and as it had resulted in no clinical improvement it was stopped. Five months following the initial presentation a sinus, with associated swelling and erythema, persisted (Fig. 2) and hence the upper cervical, jugulodigastric and facial nodes were removed in continuity with the sinus track and overlying skin. Histological reports were similar to earlier biopsies. A partial mandibular branch paresis was evident immediately postoperatively. However, this settled over the

Case report Case I A 6-year-old boy was referred by his general practitioner with a swelling in the left submandibular region. It had increased in size over the previous 6 weeks and on presentation was firm and measured approximately 10 x 8 cm. It was erythematous and slightly tender to palpation. Systemic enquiry proved unremarkable and there had been no known contacts with TB. A full blood count and chest radiograph were normal. The patient was admitted and a course of amoxycillin prescribed. Ultrasound showed a well defined hypoechoic lobulated mass consistent with an abscess although a lymphoma could not be excluded. The mass was examined under general anaesthesia when a large necrotic lymph node was found. Incisional biopsies and a swab were taken and the wound was left open for drainage. The histological appearance was consistent with tuberculosis although no acid fast bacilli were seen on microscopy. Rifampicin and isoniazid were prescribed prior to definitive typing of the mycobacterium. There proved to be a poor 511

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ments this was delayed for a period of 3 weeks during which the overlying skin became red, inflamed and infected. Histopathological

examination showed a marked epi-

thelioid granulomatous reaction with diffusely infiltrating lymphocytes, many Langhan’s giant cells and marked caseous necrosis. No acid fast bacilli were seen on microscopy. Postoperatively she made a good recovery with no sign of recurrence although there was some degree of hypertrophic scarring. Material cultured at the time of the procedure failed to provide a definitive microbiological

diagnosis after 8 weeks culture. DISCUSSION

Fig. 1 - Photograph of left submandibular region 10 weeks after initial presentation and incisional drainage.

Fig. 2 - Photograph of infected cervical lymph nodes with an associated sinus and skin discoloration.

following 4 weeks. There was no recurrence and he was reviewed until the scar had fully resolved. Case 3

A lo-year-old girl was referred with a 4 week history of a firm but mobile submental swelling slightly to the right of midline. It appeared cystic in nature and appeared to be associated with a scar from a previous laceration. She was otherwise fit and well and an ultrasound revealed a well defined oval mass compatible with the diagnosis of either a dermoid cyst or lymph node. A full blood count, chest radiograph and systemic enquiry proved unremarkable. A provisional diagnosis of MA1 was made and an

excision biopsy planned. Due to the patient’s prior commit-

Mycobacteria are non-motile, non-sporing pleomorphic rods l-5 pm long and can be separated into more than 50 species. M. avium and M. intracellulare are both slow growing mycobacteria which can not be separated by biochemical means and are therefore grouped together as MA1 complex. DNA probes are however able to differentiate these.‘j Grange et aL4 reported a series of 205 children, aged 1-13 presenting with non-tuberculous lymphadenitis where 93% of the isolates were from the cervical nodes. The remainder were found in the preauricular, axillary and inguinal regions. MA1 accounted for 82% of NTM infections whilst 8% were caused by M. malmoense. Other environmental mycobacteria isolated included M. scrofulaeceum, M. kansasii, M. chelonae and M. fort&urn. A comparable series is also reported by Lai.’ The precise mode of transmission of nontuberculous mycobacteria is unknown although epidemiological evidence suggests infection may arise from environmental sources such as soil, water, dust and aerosols. This may explain why those presenting with cervical adenitis due to MAI infection tend to be children as they are more likely to place contaminated objects in their mouths, infection thereby occurring via a breach in the mucus membranes of the oropharynx. Infection may also arise through the ocular mucosal membrane.* Human contact is not a factor in transmission9 and as such contact tracing is not advocated. Disseminated disease is often found in patients with AIDS. However, this presentation is more consistent with entry of the mycobacterium through the intestine.” The age of the patient affects the clinical manifestation of the disease as well as the ability to grow the organism in culture. Children between the ages of 2 and 5 years are the most common group affected with a majority of females being reported.5*7,g*” This age group also demonstrates a shorter period between the onset of symptoms and diagnosis and is also more likely to have MA1 isolated in culture. NTM lymphadenitis does not usually manifest with systemic signs. However, a low grade fever may be present before the development of a unilateral, insidious swelling in the cervicofacial region.gY12 This typically increases in size over a period of 5 weeks prior to presentation. l3 The superior cervical, submandibular and preauricular lymph nodes are the most commonly involved. ‘,12,14 Early in the course of the

Cervical Table

1 -Differentiating

non-tuberculous

mycobacterial

Mycobacterium

Position

of lesion

History of TB contact Chest radiograph lntradermal skin test -5TU PPD M. avium sensitin Histology

Response

to chemotherapy

Usually unilateral Superior cervical No Unremarkable

infections

from

4.3 * 1.3 mm 15.2f1.4mm Ill defined granulomas Irregular granulomas A non-specific granulomatous Sarcoid like granulomas Lack of significant caseation Poor

Mycobacterium

response

disease the nodes tend to be painless and firm often appearing to be fixed to deeper tissues. Frequently one large and several smaller satellite glands are palpated early in the course of the infection; however, they tend to become less distinct and may appear to coalesce to form a larger fluctuant mass. The overlying skin becomes shiny and erythematous before turning purple. If untreated the skin will break down, resulting in drainage and eventually a sinus track formation. Healing after this stage is often complicated by scarring. If fluctuance does not occur then spontaneous resolution is possible.8,‘4 The infection is usually unilateral but bilateral infection may occur.12,15 The most common pathogen implicated in NTM is MAI. However, this needs to be distinguished from M. tuberculosis infections (Table 1). Other conditions which need to be considered in the differential diagnosis include pyogenic adenitis, cat scratch disease, lymphoma, congenital cysts, infectious mononucleosis, sarcoidosis, actinomycosis and toxoplasmosis. The key to successful management is to establish an early diagnosis. As shown in the case reports this may prove difficult and as such the use of microscopy, histology, culture and skin testing have all been advocated. Microscopy may be informative as all mycobacteria demonstrate acid fast bacilli with ZiehlNeelsen stain. However, this is not specific for NTM infections and false positives have been reported.” Furthermore, the number of NTM mycobacteria present in biopsy tissue samples are so negligible that acid fast smears are often negative and if positive are indistinguishable from tuberculosis. Histological examination has also been reported to be non-specific.2~“,‘2.‘6 However, Pinder and Colville state that certain histological features of NTM infections are helpful in differentiating them from tuberculosis.‘* These include ill-defined and irregular or serpiginous granulomas, a predominantly nonspecific granulomatous response, predominantly sarcoid like granulomas or the lack of any significant caseation. Definitive diagnosis is therefore best achieved by culture in Lowenstein-Jensen medium although the use of polymerase chain reaction techniques may provide faster and more accurate results in the

in children

513

TB

avium-intracellulare

and submandibular

lymphadenitis

nodes

tuberculosis

Often bilateral Posterior triangle and supraclavicular nodes Yes Signs of active parenchymal disease, e.g. consolidation, cavitation, calcification 19.7*1.4mm 10.3* 1.5 mm Coalescent granulomas Epithelioid cells surrounded and lymphocytes Langhan’s giant cells Caseation Good

by fibroblasts

future.“,19 All mycobacteria are obligate anaerobes and grow best in 5510% CO,, a neutral pH and between 35 and 37°C. However, isolation of MAI takes 3-12 weeks depending upon the inoculum size.*%13 Furthermore, cultures may be negative despite infection being present such that positive culture rates ranging from 44% to 79% have been reported. 2,5,13,15*17An increased yield occurs when the diseased gland is small, when the history of the lymphadenopathy is brief.i3 and when the child is between 2 and 5 years old.” Preoperative intradermal skin testing with tuberculin purified protein derivative (PPD) and nontuberclous mycobacterium antigens has been advocated to expedite the diagnosis and management 16,17.20Joshi15 reported that in a series of 39 children who were culture positive for NTM, 90% demonstrated a positive reaction to skin testing with non-tuberculous mycobacterial antigens. A positive skin test to NTM antigens can be determined by the level of induration present after 48-72 hours, although cross reactivity between different mycobacteria species frequently occurs.‘,” However, in dual tests Fordham von Reyn2’ reported that the size of the M. avium reaction exceeded that of the PPD reaction in all patients tested (Table l), therefore, allowing some means of differentiation between NTM and hf. tuberculosis infections. Non-tuberculous mycobacterial lymphadenitis is best treated by complete surgical excision such that the atrophic skin, subcutaneous abscesses and associated lymph nodes are all eliminated and the incision closed primarily.21 However, the success of this may be dependent upon the anatomical position of the lesion and on how advanced the infection is. Parotid swellings and those close to the marginal mandibular branch are particularly prone to nerve injury22 and hence careful dissection is necessary to minimize risk of neuropraxia or division of the nerve. Currettage, incision and drainage and FNA are all associated with a greater risk of recurrence” and may encourage the formation of a chronic sinus or scarring and hence should be avoided if possible.2*9.‘2.21 If anatomical considerations require their use a second definitive procedure may be needed once further resolution has occurred, as was illustrated in Case 2.

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Antituberculous drugs are usually ineffective2,5,15~23 even in cases where chemotherapy may be indicated by means of an in vitro organism sensitivity test.r2,r6 When used in isolation they have been found to result in the formation of a chronic draining sinus or prominent scar. l2 However, as illustrated with Case 1, they may play a role in cases of incomplete excision,‘Tz4 or in preventing possible dissemination and fistula formation in patients where tuberculosis has not been excluded.” The use of clarithromycin, azithromycin and ethambutol has been proposed as a means of complementing suboptimal surgery in disease attributed to MAI25326 although some spontaneous resolution may be expected regardless of medical intervention8 It is this unpredictable feature of the disease which may have been responsible for the ultimate resolution in Case 1. In conclusion, clinicians should be aware that a chronic lymphadenopathy presenting in a child who has not been in contact with tuberculosis, who shows no or only a slight reaction to a tuberculin skin test and is unresponsive to antibiotics or antituberculous chemotherapy is highly suggestive of a nontuberculous mycobacterium infection. As the number of reported cases involving MA1 is increasing it is important that it is included as a differential diagnosis in children presenting with lymphadenitis. This is imperative as early diagnosis and effective surgical treatment minimize the risks of complications and an earlier resolution of the infection can be achieved.

11. 12 13

14. 15 16.

17.

18.

19. 20.

21. 22.

References 1. Grange JM, Yates MD. Infections caused by opportunist mycobacteria: a review. J R Sot Med 1986; 19: 226-229. 2. Margileth AM, Chandra R, Altman RP. Chronic lymphadenopathy due to mycobacterial infection: Clinical features, diagnosis, histopathology and management. Am J Dis Child 1984; 138: 9177922. 3. Alessi DP, Dudley JP. Atypical mycobacteria-induced cervical adenitis: Treatment by needle aspiration. Arch Otolaryngol Head Neck Surg 1988; 114: 664-666. 4. Grange JM, Yates MD, Pozniak A. Bacteriologically confirmed non-tuberculous mycobacterial lymphadenitis in south east England: a recent increase in the number of cases. Arch Dis Child 1995; 72: 516-517. 5. Wolinsky E. Mycobacterial lymphadenitis in children: A prospective study of 105 nontuberculous caseswith long-term follow-up. Clin Infect Dis 1995; 20: 954-963. 6. Haas WH. Kirschner P. Ziesine S. Bremer HJ. Botteer EC. Cervical lymphadenitis in a chid caused by a previo\sly unknown mycobacterium. J Infect Dis 1993; 167: 2377240. 7. Lai KK, Stottmeier KD, Sherman IH, McCabe WR. Mycobacterial cervical lymphadenopathy, Relation of etiologic agents to age. JAMA 1984; 251: 128661288. 8. Starke JR. Nontuberculous mycobacterial infections in children. Adv Pediatr Infect Dis 1992; 7: 123-159. 9. Dhooge I. Dhooae C. DeBaets F. Van Cauwenberae P. Diagn&tic and therapeutic management of atypical mycobacterial infections in children. Eur Arch Otorhinolaryngol 1993; 250: 387-391. 10. Rotterdam H, Sommers SC. Alimentary tract biopsy lesions in

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the acquired immune deficiency syndrome. Pathology 1985; 17: 181-192. Benjamin DR. Granulomatous lymphadenitis in children. Arch Path01 Lab Med 1987; 111 i 750-753. White MP. Bangash H. Goel KM. Jenkins PA. Nontuberculous mycobacterial lymphadenitis. Arch Dis Child 1986; 61: 368-371. Spark RP, Fried ML, Bean CK, Figueroa JM, Crowe P, Campbell DP. Nontuberculous mycobacterial adenitis of childhood; The ten-year experience at a community hospital. Am J Dis Child 1988: 142: 106-108. Wolinsky E. Mycobacterial diseases other than tuberculosis. Clin Infect Dis-1992; 15: l-12. Joshi W. Davidson PM. Jones PG. Camnbell PE. Roberton DM. Non-tuberculous mycobacterial fymphadenitis in children. Eur J Pediatr 1989; 148: 751-754. Cox HJ, Brightwell AP, Riordan T. Non-tuberculous mycobacterial infections presenting as salivary gland masses in children: investigation and conservative management. J Laryngol Otol1995; 109: 525-530. Huebner RE, Schein MF, Cauthen GM, Geiter LJ, O’Brien RJ. Usefulness of skin testing with mycobacterial antigens in children with cervical lymphadenopathy. Pediatr Infect Dis J 1992; 11: 450-456. Pinder SE, Colville A. Mycobacteria cervical lymphadenitis in children: can histological assessment help differentiate infections caused by non-tuberculous mycobacteria from Mycobacterium tuberculosis? Histopathology 1993; 22: 59-64. Colville A. Retrospective review of culture-positive mycobacterial lymphadenitis casesin children in Nottingham, 1979-1990. Eur J Clin Microbial Infect Dis 1993; 12: 192-195. Fordham von Reyn C, Green PA, McCormick D, Huitt GA, Marsh BJ, Magnusson M, Barber TW. Dual skin testing with Mycobacterium avium sensitin and purified protein derivative: An open study of patients with M. avium complex infection or tuberculosis. Clin Infect Dis 1994; 19: 15520. Taha AM, Davidson PT, Bailey C. Surgical treatment of atypical mycobacterial lymphadenitis in children. Pediatr Infect Dis 1985; 4: 6644667. Mitchell DA, Ord RA. Atypical Mycobacterial infection presenting as a parotid mass in a child. J Craniomaxillofac Surg 1988; 16: 221-223. Olley SF. Suppurative cervical adenitis caused by opportunist my&bacterium. Br J Oral Surg 1977; 14: 257-263. - Wallace RJ. Swenson JM. Silcox VA. Bullen MG. Treatment of nonpulmonary infections due to Mycobacterium fortuitum and mycobacterium chelonei on the basis of in vitro susceptibilities. J Infect Dis 1985; 152: 500-514. Green PA, Fordham von Reyn C, Smith RP. Mycobacterium avium complex parotid lymphadenitis: Successful therapy with clarithromycin and ethambutol. Pediatr Infect Dis J 1993: 12: 6155616. Clark JE, Magee JG, Cant AJ. Non-tuberculus mycobacterial lymphadenopathy. Arch Dis Child 1995; 72: 1655166.

The Authors M. S. Falworth BDS, FDSRCS (Eng) Senior House Officer M. T. Simpson MB BS, MRCS, FFDRCS Consultant Department of Maxillofacial Bedford Genera1 Hospital Kempston Road Bedford MK42 9DJ, UK

Surgery

Correspondence and requests for offprints to Mr M. T. Simpson. Paper received 3 November 1995 Accepted 2 April 1996