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Rheumatology Advance Access originally published online on July 22, 2006
Rheumatology 2007 46(2):280-284; doi:10.1093/rheumatology/kel206
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© The Author 2006. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Non-tuberculous mycobacterial infection in patients with systemic lupus erythematosus

M. Y. Mok, S. S. Y. Wong1, T. M. Chan, D. Y. T. Fong2, W. S. Wong and C. S. Lau

University Department of Medicine, 1Department of Microbiology and 2Department of Nursing Studies, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China

Correspondence to: Dr Mo Yin Mok, Rheumatologist, Division of Rheumatology, University Department of Medicine, Queen Mary Hospital, Hong Kong, China. E-mail: mymok{at}netvigator.com


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objectives. Patients with systemic lupus erythematosus (SLE) are susceptible to opportunistic infections. To examine the clinical manifestations of non-tuberculous mycobacterial (NTM) infections with those of Mycobacterium tuberculosis (MTB) infections in SLE patients.

Methods. Medical records of a cohort of 725 SLE patients were reviewed for previous NTM infections. Demographic characteristics, predisposing factors and clinical outcomes were compared with patients who had previous MTB infections (n = 39).

Results. Eleven (nine female and two male) cases were identified (prevalence 1.5%). The mean ± S.D. age at the time of infection was 42.8 ± 13.9 yrs, 9.3 ± 5.8 yrs after the onset of SLE. The mean ± S.D. time taken from onset of symptoms to the diagnosis of NTM infection was 5.7 ± 7.2 months. Sites of involvement included skin and soft tissue (n = 8), chest (n = 2) and disseminated infection (n = 1). NTM infections were more likely to involve extrapulmonary sites (P = 0.006), presented in patients with longer lupus disease duration (P < 0.001), occurred in older patients (P < 0.001) and in those who had a higher cumulative dose of prednisolone (P = 0.01) than MTB infections. Using a stepwise logistic regression, disease duration was found to be the only independent predictive factor (P = 0.005) for NTM infections. Ten (25.6%) patients with MTB infections but none of the patients with NTM infections presented concomitantly at the onset of SLE (P = 0.09). There were no differences in the recurrence rate (P = 0.64) and frequency of disseminated infections (P = 0.40) between NTM and MTB infections.

Conclusions. NTM infections tended to develop in SLE patients later in their disease course than MTB infections. A high index of suspicion is required for its diagnosis.

KEY WORDS: Infection, Immunocompromised host, Mycobacterium, Synovitis


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 References
 
Non-tuberculous mycobacteria (NTM) are ubiquitous microorganisms in the environment. They are not common causes of invasive diseases in immunocompetent individuals. Serious infections due to NTM are more commonly encountered in immunocompromised hosts such as organ transplant recipients and patients with acquired immunodeficiency syndrome (AIDS) [1]. NTM infections have also been described in patients with autoimmune diseases in isolated case reports, especially in those with systemic lupus erythematosus (SLE). In this article, we present the largest series of NTM infections from our SLE cohort. We describe the clinical manifestations of NTM infections in these patients and compare their clinical course and risk factors with Mycobacterium tuberculosis (MTB) infections, which are endemic in our region.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 References
 
Medical records of patients who satisfied the 1982 revised classification criteria for SLE [2] were reviewed. These patients belonged to an inception cohort that had been followed up at a university-affiliated rheumatology clinic in Hong Kong since 1985. Cases of NTM infections are ascertained with a positive culture and documented follow-up were identified. Demographic characteristics, lupus clinical manifestations and treatment at the time of NTM infection and details of the clinical course of the NTM infection including the site of infection, treatment and clinical outcomes were recorded. Clinical data from 39 patients with MTB infection from the same cohort was used for comparison.

Statistical analysis was done using SPSS 11.0 software (Chicago, IL, USA). Comparisons were made on the demographic characteristics, predisposing factors to infection and clinical outcomes between patients with NTM and MTB infections. A chi-square test was used for comparison of categorical data. The Mann–Whitney U-test was performed for continuous data analysed. These were then examined in a forward stepwise logistic regression analysis for their independent effects on the development of NTM or MTB infection. A P-value of <0.05 was considered as statistically significance.


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 References
 
There were 725 SLE patients in the cohort. The mean ± S.D. duration of follow-up was 10.0 ± 6.8 yrs. A positive culture of NTM was identified in 14 patients. In three patients, the positive growth was considered to be colonization as the patients were asymptomatic and repeated cultures were negative.

The demographic characteristics and clinical features of NTM infections of the 11 ascertained cases are shown in Table 1. There were nine female and two male patients. The mean ± S.D. age at the onset of SLE was 33.6 ± 14.2 yrs. They had been followed up for 11.6 ± 7.0 (median 10) yrs. The lupus manifestations in these patients included polyarthralgia (100%, n = 11), malar rash (63.6%, n = 7), nephritis (63.6%, n = 7), serositis (63.6%, n = 7), autoimmune haemolytic anaemia (45.5%, n = 5), leucopenia (36.4%, n = 4), thrombocytopenia (36.4%, n = 4), discoid rash (36.4%, n = 4), oral ulceration (36.4%, n = 4) and cerebral involvement (18.2%, n = 2). These patients had other comorbidities including IgA deficiency (n = 3), bronchiectasis (n = 2) and diabetes mellitus (n = 1). The mean ± S.D. age of these patients at the time of NTM infection was 42.8 ± 13.9 (median 42) yrs after follow-up of 9.3 ± 5.8 yrs since the onset of SLE. Most patients had mild-to-moderately active lupus at the time of NTM infection. The mean ± S.D. SLE disease activity index (SLEDAI) was 5.6 ± 2.8 (median 6, range 2–10). All but one patient were receiving prednisolone (median dose 10 mg/day, range 0–50 mg/day) and four were taking azathioprine. Lymphopenia was found in six patients with available data on lymphocyte count. Some patients also had hypoalbuminaemia (serum albumin ≤35 mg/dl) (n = 5), impaired renal function (n = 3) and significant proteinuria (n = 3) at the time of NTM infection.


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  		TABLE 1. Demographic characteristics and clinical features of patients with systemic lupus erythematosus (SLE) complicated by non-tuberculous mycobacterial (NTM) infection

 
The time between the onset of symptoms to diagnosis of NTM infection varied from 1 day to 24 months (mean ± S.D. 5.7 ± 5.8, median 3.0 months). Soft tissue and cutaneous involvement was most frequent (#1–8) and may present as skin nodules or abscesses (n = 4), skin ulcers (n = 2) and acute synovitis (n = 2). M. chelonae (n = 3), M. avium–M. intracellulare complex (MAC) (n = 1), M. fortuitum (n = 1) and M. haemophilum (n = 1) were the infective agents involved. Pneumonia by MAC occurred in two patients (#9 and 10). Both had pre-existing bronchiectasis and presented with haemoptysis and new chest X-ray (CXR) shadows. The organism was grown from bronchoalveolar lavage. One patient (#11) had disseminated disease from M. kansasii infection resulting in pneumonia, cervical lymphadenitis and multifocal osteomyelitis.

Most patients showed satisfactory response to treatment with anti-mycobacterial agents including amikacin, clarithromycin and imipenem. The duration of treatment varied from 10 weeks to 3.5 yrs depending on the site of involvement. One patient developed a paradoxical reaction after treatment with new crops of cutaneous lesions but negative growth from the aspirate. There was no NTM infection-related mortality. There were two recurrences 2 months and 3 months after cessation of treatment.

The clinical manifestations and the course of NTM infection in these SLE patients were compared with those of MTB infection in the same cohort (Table 2). Extra-pulmonary involvement was more common in NTM (83.3%) than in MTB infection (33.3%) (P = 0.006). Extra-pulmonary tuberculosis manifested as lymphadenitis (n = 3), meningitis (n = 3), synovitis (n = 3), skin ulcer (n = 1), endometritis (n = 1), urinary tract infection (n = 1) and disseminated disease (n = 1). Soft tissue and cutaneous involvement was seen in 72.7% (9/11) of NTM infections but in only 30.8% (4/13) of the extrapulmonary MTB infections. The rate of disseminated disease was not different between NTM (9.1%) and MTB (2.6%) infections (P = 0.40). MTB infections were found to develop earlier (3.7 ± 4.0 yrs, median 3 yrs) in the clinical course than NTM infections (9.3 ± 5.8 yrs, median 7 yrs) (P < 0.001). Ten patients had concomitant MTB infection complicating the first manifestation of SLE whereas no NTM infections were seen at the onset of SLE. The recurrence rates of NTM (16.7%) and MTB (12.2%) infections were similar (P = 0.65). There was no infection-related mortality from NTM and MTB infections in this series.


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  		TABLE 2. Comparison of clinical characteristics and potential predisposing factors to non-tuberculous mycobacterial (NTM) and Mycobacterium tuberculosis (MTB) infection

 
Predisposing factors to infection were compared between patients with NTM and MTB infections. NTM infections were more likely to occur in patients who had received a higher cumulative dose of prednisolone (25.82 ± 20.05 g, median 25.53 g) than MTB infections (11.58 ± 14.77 g, median 5.73 g) (P = 0.01). Patients who had NTM infections developed the infection at an age older than those who had MTB infections (P < 0.001). There were no differences in the number of patients who had hypoalbuminaemia (P = 0.49), significant proteinuria (P = 0.72), daily dosage of prednisolone (P = 0.34) and azathioprine (P = 0.62) between patients with NTM or MTB infections. In the forward stepwise logistic regression analysis, only duration of SLE at infection remained statistically significant (P = 0.005).


   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
References
 
In our cohort, soft tissue and skin were the predominant sites of involvement by NTM and clinically manifested as local or disseminated skin nodules or abscesses. Chronic skin ulcers and cellulitis were also occasionally seen [3, 4] and may mimic lupus-related cutaneous vasculitis [5]. Local implantation of the organism from skin abrasion was likely to be the route of transmission as most NTM are found in water and soil. Apart from M. chelonae viz MAC and M. haemophilum as reported here, other NTM have also been described to cause cutaneous infections in SLE (reviewed in [5]). M. haemophilum, which is commonly reported in patients on renal dialysis, was the causative agent in our patient (#6) who had significant impairment of renal function. Acute synovitis, in particular single joint involvement, should raise clinical suspicion for an infective cause in patients with SLE. Apart from M. fortuitum and MAC reported here, M. marinum has also been reported in patients previously exposed to seawater [6]. Infections of joint and periarticular tissues like bursitis [7–10] and osteomyelitis [11, 12] were also reported to be caused by NTM in SLE patients.

MAC may cause pneumonia, lymphadenitis and occasionally disseminated disease in severely immunocompromised individuals and may present with atypical manifestations such as haemophagocytosis [13] and cerebral disease [14]. The clinical presentations of haemoptysis, new CXR shadows and positive growth from bronchoalveolar lavage supported as active infection rather than colonization in our patients. MAC infection typically manifests in the later stages of AIDS when patients are profoundly immunosuppressed, but the two patients in our cohort had only mild lymphopenia and were not heavily immunosuppressed at the time of infection. Likewise, one of our patients who were on low dose prednisolone developed disseminated M. kansasii infection. She also had concomitant Salmonella infection at the onset of the NTM infection and human immunodeficiency virus (HIV) infection has been excluded. Disseminated disease due to M. kansasii is often seen in heavily immunocompromised hosts such as HIV-infected individuals. As immunity against mycobacterial infection depends significantly on macrophage activation and the production of cytokines including interferon-{gamma} (IFN-{gamma}) and interleukin-12 [15], patients with heterozygous or homozygous mutations of receptors to these cytokines have been reported to develop NTM and/or MTB infections [16, 17]. It is also possible that NTM infections in SLE patients who are not heavily immunosuppressed may have an acquired deficiency of IFN-{gamma} due to the production of autoantibodies to IFN-{gamma}, which has been reported in one patient with organ-specific autoimmune disease [18].

NTM and MTB demonstrated different clinical behaviours among our SLE patients. Tuberculosis is mostly a pulmonary disease and extrapulmonary tuberculosis occurred in 33.3% of our cohort and may manifest as synovitis, skin ulcer and lymphadenitis, which clinically cannot be differentiated from NTM infections. Definitive diagnosis requires tissue biopsies for identification of the organism. As most NTM are naturally resistant to conventional anti-tuberculous medications, treatment regimen depends on the in vitro susceptibility testing results of the inciting organism. Clarithromycin, amikacin and imipenem are commonly used for rapid growers while clarithromycin is the mainstay of treatment for MAC. Most patients in our cohort showed satisfactory clinical response with no recurrences. Disseminated disease was uncommonly seen in infection by both mycobacteria.

MTB infection was found to occur earlier in the clinical course of SLE than NTM infection. The different timing of occurrence of infection by the two mycobacteria during the course of SLE was likely to be related to the different levels of immunosuppression of these patients. The longer duration of follow-up with the associated higher cumulative dose of prednisolone in patients with NTM infections may suggest that these infections occurred in more immunocompromised SLE patients than MTB infection. This is reminiscent of the situation in HIV-infected patients where tuberculosis usually develops at an earlier stage than NTM infections during the course of HIV infection. Only rarely has mortality been reported in NTM infection in SLE patients [19].

It is interesting to note that 10 patients had concomitant tuberculosis at the onset of SLE, whereas none of the NTM infections was seen at lupus onset in our series. NTM infection has only been reported at first manifestation of SLE in a single case report [20]. It remains to be elucidated whether the immunity involved in controlling MTB infection like IFN-{gamma} could have precipitated the first manifestation of SLE in susceptible person. An alternative postulation was that the cytokine millieu found in active SLE at lupus onset could have led to an immunodeficient state that rendered the patient susceptible to MTB infection.

In conclusion, the prevalence of NTM infections of 1.5% in our lupus cohort suggests that this disease is not uncommon in this group of patients. Most NTM that cause disease involved the lungs, skin, soft tissue, lymph node, bone or may rarely disseminate. The clinical manifestations of NTM infection in our SLE cohort followed the same pattern of involvement though there were fewer cases of lymphadenitis. The presentation may be insidious in onset, have different sites of involvement and present as multifocal lesions. Tissue culture is often required for a definitive diagnosis as the clinical manifestations of NTM infections are not pathognomonic and may mimic other infective or non-infective conditions. A high index of suspicion should be raised when there are atypical manifestations and when the clinical response to empirical antimicrobial therapy is unsatisfactory. NTM infections tend to occur in the chronically and more heavily immunosuppressed SLE patients as compared with tuberculosis. It may cause significant morbidity with clinical recurrences but mortality is not likely.

Formula

The authors have declared no conflicts of interest.


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

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  19. Laborde H, Rodrigue S, Catoggio PM. (1989) Mycobacterium fortuitum in systemic lupus erythematosus. Clin Exp Rheumatol 7:291–3.[Web of Science][Medline]
  20. Takada K, Suzuki K, Kataharada K, et al. (2004) A patient with a Mycobacterium avium complex infection complicated by systemic lupus erythematosus. J Infect Chemother 10:49–52.[CrossRef][Medline]
Submitted 13 February 2006; revised version accepted 12 May 2006.
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This Article
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