Submandibular lymphadenitis due to Mycobacterium malmoense: first reported case from Greece

Abstract

An 8-year-old girl with subacute submandibular lymphadenitis and no other complaints is described. After failure of parenteral antistaphylococcal therapy, she underwent incision and drainage of the involved lymph node. The responsible pathogen was identified as Mycobacterium malmoense by GenoType CM assay and sequencing of the 16S ribosomalRNA (rRNA) gene. The patient remains healthy, 11 months after surgery, even though it took approximately 4 months for the surgical incision to heal completely. While M. malmoense is a relatively common cause of non-tuberculous mycobacteria (NTM) lymphadenitis in Northern Europe, this is the first reported case from Greece. We conclude that in a young child with lymphadenitis without systemic symptoms, the microbiology laboratory should be notified in advance in order to extend the duration of mycobacterial cultures. Application of molecular methods will increase the number of reported cases of rare NTM in the future.

Background

The genus Mycobacterium contains Mycobacterium tuberculosis, Mycobacterium leprae and the so-called non-tuberculous mycobacteria (NTM). NTM are commensal saprophytes. Most of them are non-pathogenic, but some can cause human disease. In North America and Europe, NTM have emerged as the most frequent cause of subacute or chronic lymphadenitis in children. These low-virulence, acid-fast bacilli are ubiquitous in soil, water, food and air. Cervicofacial lymphadenitis is the most common presentation in children, followed by inguinal and axillary disease.¹ We present an 8-year-old girl with submandibular lymphadenitis due to M. malmoense, the first such case reported from Greece.

Case presentation

An 8-year-old previously healthy girl without risk factors for tuberculosis was seen by her paediatrician because of a painless submandibular swelling of a few days’ duration. She was afebrile and had no other complaints. She was prescribed oral amoxicillin, but due to no improvement she visited our hospital 2 weeks later. At that time, a left submandibular non-tender lymph node measuring approximately 3.4 cm with rubbery texture was palpated, while erythema of the overlying skin was noted. She continued to be afebrile, was fully immunised, had a negative purified protein derivative skin test and a normal chest radiograph. Dietary, contact, travel and family history were unremarkable.

She was admitted in order to receive a course of intravenous cefuroxime, but because of progressive fluctuation of the involved lymph node, she was eventually taken to the operating room approximately 1 month after the initial presentation. In the operating room, an incision and drainage were performed, pus was sent for cultures, while the microbiology laboratory was notified of our clinical suspicion for atypical mycobacterial lymphadenitis.

Investigations

Approximately 8 weeks after surgery, an acid-fast organism was slowly growing from the submitted pus on Löwenstein-Jensen medium. The organism was subcultured in solid Löwenstein-Jensen medium and liquid Bactec MGIT 960 mycobacterial detection systems (Becton Dickinson, Sparks, Maryland, USA). Identification of the organism as Mycobacterium malmoense was performed by molecular hybridisation using the GenoType CM assay (Hain Lifescience, Nehren, Germany), and confirmed by sequencing of the 16S rRNA gene. In vitro antibiotic susceptibility testing showed the recovered strain to be sensitive to clarithromycin, ethambutol, ciprofloxacin, levofloxacin, moxifloxacin and linezolid and resistant to rifampicin and cotrimoxazole.

Differential diagnosis

Staphylococcal or streptococcal lymphadenitis, cat scratch disease (CSD), mumps, Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infection. CSD was considered unlikely, since there was no history of contact with cats. Staphylococcal and/or streptococcal lymphadenitis are usually associated with fever and/or systemic symptoms and typically respond to appropriate antibiotic therapy. Mumps was excluded because the swelling was not in the anatomical area of the parotid gland, and moreover it was unilateral. Finally, infections with EBV and CMV are associated with lymphadenopathy rather than purulent lymphadenitis.

Treatment

Postoperatively the patient recovered well and was sent home without further antibiotics. Pending identification of the recovered pathogen, she was reexamined 2 months after surgery due to minimal drainage of the surgical incision. At that time, an empirical 1-month course of oral cotrimoxazole was prescribed along with local antiseptic wound care.

Outcome and follow-up

The surgical incision healed, and the drainage stopped around the time that the pathogen’s identification was available to us, that is, almost 4 months postoperatively. The patient remains healthy, 11 months after surgery.

Discussion

M. malmoense was first described by Schröder and Juhlin in 1977 in four patients with pulmonary disease from Malmo, Sweden.² Two main groups of patients with disease attributed to M. malmoense were identified in a study of 221 Swedish patients, that is, adults with pulmonary infection and children with lymphadenitis.³ Extrapulmonary and disseminated disease is extremely uncommon. In Sweden, M. malmoense is second only to the Mycobacterium avium complex (MAC) as a cause of atypical mycobacterial infection. Later on, this organism emerged in UK as a cause of MAC-like pulmonary disease in adults, and as a rare cause of NTM lymphadenitis in children. Claesson et al described 126 previously healthy children with NTM lymphadenitis treated at Karolinska Hospital in Stockholm.⁴ Overall, 105 cultures yielded MAC, and 12 M. malmoense. Time from onset of symptoms to diagnosis of NTM lymphadenitis was <3 months in 76% of the children, while time to healing was >6 months in a significantly larger proportion of the non-surgically treated children compared with those who underwent surgery (25% vs 3%). Re-operation was performed in 6% of cases. Major persisting nerve dysfunction occurred in 3 of 51 (6%) children who underwent radical surgery, while minor nerve dysfunction occurred in seven (14%) children. In contrast, there were no neurological signs in 25 children treated with incision and drainage alone or in 12 followed with observation alone. Healing took >6 months in 2 of 76 (3%) surgically treated children and in 3 of 12 (25%) non-surgically treated ones. Grange et al studied the number of cases of NTM lymphadenitis in South East England between 1973 and 1993.⁵ Among 205 cases, 17 were caused by M. malmoense, all occurring after 1980. In fact, M. malmoense was the only species for which a significant increase was noted over time.

Although relatively common in Scandinavia and Northern Europe, M. malmoense has to date been isolated only rarely in Southern Europe. Tortoli et al described 10 clinically significant isolates of M. malmoense from Italy in 1997, four of whom were from children with cervical lymphadenopathy.⁶ In addition, López-Calleja et al reported two more cases of M. malmoense lymphadenitis in immunocompetent children from Spain.⁷ To the best of our knowledge, our patient is the first reported paediatric case from Greece. Regarding Greece, M. malmoense has previously been isolated from adults with clinically significant lung infection in Central Greece.⁸ In the only other relevant paediatric publication from Greece, Maltezou et al reviewed 47 children 0 to 14 years of age with NTM lymphadenitis who were treated at Greece’s largest tertiary paediatric centre in Athens over a 16-year period.⁹ Cultures for mycobacteria identification were undertaken in 45 patients and were positive in 40 patients. MAC was detected in 33 patients and Mycobacterium kansasii in three patients, while in four patients, NTM were detected but no specific identification method was applied. A systematic review by Heraud et al of 1915 children with NTM lymphadenitis in the head and neck region showed that M. malmoense was the third most common species following MAC and Mycobacterium haemophilum, and responsible for 4.9% of the cases.¹⁰ In another review by Zimmermann et al of 1274 clinical isolates of NTM lymphadenitis in childhood, 42 or 3% were M. malmoense following only MAC (963 or 76%) and M. haemophilum (77 or 6%) and prevailing over M. kansasii (n=26 or 2%) as the causative agent.¹¹

The first reported case of lymphadenitis due to M. malmoense in the USA, a 5-year-old boy with cervical and submandibular lymphadenopathy that was cured with surgery alone was described by Buchholz et al in 1998.¹² In contrast with adults, where isolation of M. malmoense from only one respiratory specimen does not usually signify disease but colonisation of the respiratory tract, isolation of M. malmoense from pus in children aged <10 years with cervical lymphadenitis is indicative of a causal relationship. McCrossin and Mailman reviewed a decade of experience with NTM lymphadenitis at a Canadian paediatric referral centre. In their review, the first two paediatric Canadian cases of M. malmoense NTM lymphadenitis were described.¹³ They noted that patients often receive multiple ineffective antibiotic courses mainly with anti-staphylococcal antibiotics prior to diagnosis, and that delays in diagnosis and referral for appropriate therapy are very common. The main clinical features in their study included a mean age at presentation of 3.4 years, a male-to-female ratio of 1:1.5 and a gradual onset of painless, unilateral cervical adenopathy. It is of note that fever was absent in 77% of the patients, while the mean time to correct diagnosis was >3 months.

As it is the case with other NTM, the typical patient with lymphadenitis is usually a healthy Caucasian child, most commonly girl, 2 to 5 years old with unilateral lymphadenopathy of the superior cervical lymph nodes. The patient usually has no systemic signs or symptoms like our patient. The affected lymph nodes are typically firm, elastic and non-tender with erythema of the overlying skin, but with therapeutic delay they soften, and can rupture spontaneously and drain, often forming a persistent sinus.

In cases of NTM lymphadenitis, histopathology often documents supportive but non-specific changes, such as granuloma formation. However, it is vital in ruling out lymphomas or other malignancies. Histopathology cannot differentiate between the various microbial causes of granuloma formation neither it can distinguish M. tuberculosis from other acid-fast NTM species. On the other hand, culture diagnosis has poor sensitivity and an extremely slow turnaround time, making timely clinical decisions impossible. M. malmoense is a non-pigmented mycobacterium under all light conditions and is among the most fastidious NTM described to date, some strains requiring up to 12 weeks of incubation, a much longer time-interval than that most laboratories hold cultures.

Increased pollution of piped water by NTM that are environmental saprophytes and weakening of the upper respiratory tract immunity by air pollution are a tempting but unproven explanation for the increased number of cases of NTM lymphadenitis in recent decades. Concerning M. malmoense, its selection within NTM may have occurred due to differences in susceptibility to disinfectants used in tap water or due to other yet unknown environmental factors.

For NTM lymphadenitis, complete surgical excision by an experienced ENT surgeon is the treatment of choice. If complete excision is not feasible or there is fear for neurological damage in the mandibular branch of the facial nerve, partial excision or incision and drainage-like in our case, with or without antibiotics, are recommended.¹

In conclusion, increased awareness of M. malmoense and other NTM along with improved identification methods will likely increase the number of reported cases in the future.

Patient’s perspective.

As the patient and her mother, we want the reader to appreciate what an uncertainty was when we were called that a slow growing organism was isolated from the submitted lymph node pus. As a mother, I appreciated the laborious efforts of the doctors to establish an accurate diagnosis by submitting the recovered organism to the University Hospital of Heraklion for molecular identification. Finally, we were impressed that the identified pathogen, a non-tuberculous mycobacterium, was initially described in patients from Sweden, and that no similar reported case exists from Greece.

Learning points.

• If the clinical scenario is suggestive of non-tuberculous mycobacteria (NTM) lymphadenitis, that is, lymphadenitis in the absence of systemic symptoms in a young child that has failed antistaphylococcal antibiotics, the microbiology laboratory should be notified in advance in order to extend the duration of mycobacterial cultures.

• Although for NTM lymphadenitis, surgical excision by an ENT surgeon is the treatment of choice, incision and drainage may be adequate.

• Application of molecular methods like the GenoType CM assay and sequencing of the 16S ribosomal RNA gene will increase the number of reported cases of rare clinically significant NTM in the future.