Cervical lymphadenitis from Mycobacterium avium complex

Abstract

We present an instructive case of cervical lymphadenitis in a young man without a history of HIV infection. The patient developed spontaneous left-sided neck swelling that progressed over 4 months. CT imaging demonstrated a necrotic left-sided neck mass within the cervical lymph node chain. He was initially prescribed azithromycin and rifampin for presumed cat scratch disease with improvement but incomplete resolution of symptoms. Blood cultures ordered 2 months later grew Mycobacterium avium complex (MAC) and the patient had an excellent clinical response to MAC therapy. Here, we review the case, including presentation and management, and describe the implications for the immune status of the host and long-term considerations for treatment.

Background

Infections due to non-tuberculous mycobacteria (NTM) are becoming more prevalent due to the pervasiveness of these organisms in the environment, as well as increasing numbers of immunosuppressed individuals.^{1 2} While pulmonary NTM infections are more commonly encountered, data regarding the prevalence of extrapulmonary NTM infections are currently limited, especially in people without HIV infection.³ There is a lack of recent epidemiological data regarding the prevalence of these infections in the adult population in the USA. NTM lymphadenitis is usually encountered in immunocompromised individuals and in those who sustain trauma or undergo surgical procedures, when NTM organisms can be inoculated into tissue.³ Most of the literature on NTM cervical lymphadenitis to date focus on the paediatric population.⁴ The degree of host immunosuppression affects clinical presentation and has significant implications for future management. Isolating Mycobacterium avium complex (MAC) from a wound culture typically implies significant host immunosuppression, while isolation of certain other NTM organisms like M. abscessus, for instance, does not, by itself, suggest immune deficiency.

Here, we describe a young man with cervical lymphadenitis from disseminated MAC. We review the relevant literature regarding medical and surgical therapies.

Case presentation

A Hispanic man in his 20s developed progressive left-sided neck swelling, with fevers, night sweats, chills and tenderness to palpation. His weight remained stable. He was born in the Caribbean and lived in the USA for most of his life. He denied any history of smoking, drug use or significant medical history including hospitalisations. At the time of these symptoms, he was unemployed, but previously worked in a service industry. Shortly after the onset of symptoms, he presented to an outside hospital where he was prescribed amoxicillin/clavulanate for 14 days, without improvement in his symptoms. Several weeks later, his systemic symptoms improved. However, he continued to have persistent and progressive neck swelling. A CT scan of the neck performed 2 months after the onset of his symptoms revealed a 3.3 × 2.3 × 3.7 cm necrotic left neck mass.

Due to a lack of improvement in his symptoms, he subsequently established care with our infectious diseases service following referral from the otorhinolaryngology clinic affiliated with our medical centre. On presentation, patient was normotensive, afebrile and had a regular heart rate. Exam was notable for a left-sided 4 cm indurated, firm and non-mobile lymph node. Chest X-ray prior to his appointment was unremarkable with clear lung findings. The initial differential diagnosis at that time included lymphoma, scrofula, Bartonella, toxoplasmosis and syphilis. He underwent an interval CT scan 4 weeks after his first, revealing an enlarged 4.3 × 3.8 × 5.3 cm necrotic mass centred in the left cervical lymph node chain with associated lymphadenopathy of the remaining cervical lymph nodes (figure 1). Fine-needle aspiration of the mass revealed necrotising granulomatous inflammation with no malignant cells. Bacterial, fungal and acid-fast bacilli (AFB) smears were negative and cultures eventually finalised as no growth. The initial workup revealed only a positive Bartonella henselae IgG antibody with a titre of 1:64. Fourth generation HIV antigen and antibody, cytomegalovirus PCR, Epstein-Barr virus PCR, interferon gamma release assay for tuberculosis antigens (QuantiFERON-TB Gold Plus), B. henselae IgM and Toxoplasma gondii IgM and IgG were all negative. Since the patient had contact with a cat prior to the onset of symptoms, he was prescribed a 10-day course of azithromycin and rifampin for possible cat scratch disease (CSD), with only slight improvement of swelling. Due to incomplete resolution of left neck swelling, AFB blood cultures were obtained 6 weeks after completion of his antibiotic course, which grew MAC after 7 days of incubation. He was then advised to present to the hospital.

Figure 1.

CT neck revealing a 4.3 × 3.8 × 5.3 cm necrotic mass (white arrow) in the left cervical lymph noted chain with associated lymphadenopathy.

In the hospital, a four-drug treatment regimen was initially started, including amikacin, azithromycin, ethambutol and rifabutin, with resolution of left-sided lymphadenopathy. Further AFB blood cultures during this admission finalised with no growth after 6 weeks. CT imaging of the chest, abdomen and pelvis with intravenous contrast did not reveal other sites of lymphadenopathy. While hospitalised, the patient developed leucopenia and neutropenia with intermittent fevers, without localising symptoms. Extensive additional infectious workup, including whole body Gallium scan, was unremarkable. Rifabutin was changed to rifampin, with improvement in both leucopenia and neutropenia. Prior to discharge, amikacin was discontinued, and azithromycin, ethambutol and rifampin were continued for a planned 18-month course of treatment.

Outcome and follow-up

Extensive primary immunodeficiency workup was performed while inpatient and on follow-up. An initially abnormal ‘Mitogen and Antigen-induced Lymphocyte Proliferation Panel,’ (Quest Diagnostics, Secaucus, New Jersey, USA) potentially consistent with a functional lymphocyte deficiency normalised when it was repeated 6 weeks later. He had a normal serum protein electrophoresis, normal immunoglobulin levels and negative granulocyte-macrophage colony-stimulating factor and anti-interferon gamma antibodies. In addition, repeat HIV testing, including viral load, was negative. CD4 count was 574 cells/mm³ (33% CD4 cells). At his latest follow-up 6 months after initiation of therapy, he remained afebrile with complete resolution of neck swelling. Follow-up CT imaging of the neck was not performed due to clinical improvement.

Discussion

We present an unusual case of cervical lymphadenitis with disseminated MAC, presenting as isolated cervical granulomatous lymphadenitis and MAC bacteraemia, in a previously healthy young man. This case demonstrates the importance of considering both the pathogen and the immune status of the host when caring for patients with a mycobacterial infection.

While the patient did not grow MAC in AFB cultures from his neck aspiration (table 1), MAC is almost certainly the aetiology of his necrotic cervical lymphadenitis since it subsequently grew in a blood culture, the pathology from the aspiration was consistent and he experienced resolution of symptoms with MAC therapy. The B. henselae IgG titre of 1:64 likely represented remote exposure or a false-positive result. In a study of 42 individuals with CSD and 270 healthy controls, all patients with CSD had an IgG titre ≥1:128 and 38/270 (14.1%) healthy controls had a titre of 1:64.⁵ To our knowledge, there is no known association between MAC disease and B. henselae titres. MAC and other NTM organisms including M. abscessus can cause isolated lymphadenitis in immunocompetent or immunocompromised hosts.⁶ However, this patient had disseminated MAC, which indicates an underlying immunodeficiency, most commonly deficient cell-mediated immunity.⁷ Specifically, the host response to MAC is dependent on CD4+ T cells and production of interferon-γ.⁷ Disseminated MAC infection has also been reported in those on tumor necrosis factor alpha (TNF-α) inhibitors.⁸

Table 1.

Features of NTM-cervical lymphadenitis in a patient with MAC

	Patient
Age at presentation	21
Sex	Male
Source of infection	Spontaneous/disseminated MAC
Organism isolated	Mycobacterium avium complex
Source of isolate	Blood
Immune status	Presumed immunodeficiency, though yet undefined (possible functional lymphocyte deficiency)
Induction/initial regimen	Intravenous amikacin 15 mg/kg/day × 2 weeks, per os (PO, by mouth) azithromycin 500 mg daily, PO ethambutol 15 mg/kg/day, and PO rifabutin 300 mg daily
Consolidation regimen	PO azithromycin 500 mg daily, PO ethambutol 15 mg/kg/day, and PO rifampin 600 mg daily
Susceptibilities	None (note susceptibilities were requested but while the organism grew initially, it did not grow in subcultures on test media)
Antibiotic course	18-month course

MAC, Mycobacterium avium complex; NTM, non-tuberculous mycobacteria.

While this patient’s presumed immunodeficiency is currently unknown, initial immunodeficiency workup was concerning for a potential functional lymphocyte deficiency. The assay used, the mitogen and antigen-induced lymphocyte proliferation panel, assesses T-cell function following the introduction of phytohaemagglutinin and pokeweed mitogens. This test allows for the evaluation of T-cell function, although the exact performance characteristics including sensitivity and the factors that may affect reliability of the test are not well described, and there is no literature of it to date as a tool for the diagnosis of immunodeficiencies or as a way to predict risk for opportunistic infections.⁹ While repeat testing normalised, deficient cell-mediated immunity would explain why he developed this infection.

Treatment for isolated MAC cervical lymphadenitis—most often seen in children under 3 years old—includes a macrolide with either ethambutol and/or a rifamycin for 6–12 months.^{10 11} Our patient had an atypical presentation, with onset much later than early childhood and with disseminated infection. While there are limited data regarding the length of treatment, we recommended treating with three agents for 18 months. We anticipate close monitoring for relapse/reinfection after completion of treatment. If he were to relapse, he would likely need a repeat 18-month course followed by life-long secondary prophylaxis with macrolide therapy; thereafter, life-long azithromycin prophylaxis is recommended for people with certain irreversible immunodeficiencies, such as idiopathic CD4+ T cell lymphopenia.¹² Since no clear immunodeficiency was identified in our patient, it is reasonable to stop antibiotics after completion of the initial 18-month course with close ongoing monitoring thereafter.

Patients who develop cervical lymphadenitis from M. abscessus or other rapidly growing NTM have a different prognosis and long-term consequences. M. abscessus and other rapidly growing mycobacteria can be introduced into wounds from contaminated water and/or soil with local trauma or non-sterile surgical procedures.¹³ Infection with M. abscessus often occurs in normal hosts without known immunological defects.¹³ Treatment includes a macrolide (if the isolate is susceptible) with amikacin and at least one additional active agent for a 6–12 months long course.¹⁴ All-oral regimens including using omadacycline instead of tigecycline are increasingly popular (and supported by accumulating clinical experience) for M. abscessus infections.¹⁵ Since M. abscessus infections are often seen in normal hosts, lifelong therapy is usually not indicated.

The management of cervical lymphadenitis secondary to NTM typically includes both medical and surgical therapy. Most case reports and case series involving surgical therapy for NTM lymphadenitis come from the paediatric literature, but guidance can potentially be extrapolated to adult populations. In cases of MAC lymphadenitis without evidence of widespread disease, surgical excision may be indicated.³ A systematic review demonstrated that surgical excision provided the highest chance (98%) for cure compared with observation (70.4%) and medical therapy (73.1%).⁴ However, surgery involves a risk of injury to branches of the facial nerve.¹⁶ Other risks include the formation of fistulas following excision, although NTM lymphadenitis can cause fistulising disease without surgical intervention.¹⁷ For NTM lymphadenitis secondary to rapidly growing mycobacteria, surgical intervention may be required if the infection is extensive. From our review of the literature, cervical lymphadenitis from M. abscessus in immunocompetent adults has only very rarely been reported to date.¹⁸ There are also rare cases of this entity in children.¹⁹ MAC is a very unusual cause of cervical lymphadenitis in adults, though the exact prevalence is unknown with more data needed to better define the specific risk factors and ideal management strategies of this condition.⁶

Learning points.

• Non-tuberculous mycobacterial (NTM) lymphadenitis is an uncommon but important cause of lymphadenitis in adults.

• NTM infections should be considered in immunosuppressed hosts and in patients with appropriate clinical history such as exposure to contaminated water through skin defects.

• Treatment involves prolonged courses of multiple different antibiotics and/or surgical resection.

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