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Rheumatology Advance Access published online on May 23, 2007
Rheumatology, doi:10.1093/rheumatology/kem102
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Recurrent major infections in juvenile-onset systemic lupus erythematosus—a close link with long-term disease damage

P. P. W. Lee, T-L. Lee, M. H.-K. Ho, W. H. S. Wong and Y.-L. Lau

Department of Paediatrics and Adolescent Medicine, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China

Correspondence to: Prof. Y.-L. Lau, Department of Paediatrics and Adolescent Medicine, Room 117, 1/F New Clinical Building, Queen Mary Hospital, Pokfulam, Hong Kong, China. E-mail: lauylung{at}hkucc.hku.hk


   Abstract
Top
 Abstract
Introduction
 Methodology
 Results
 Discussion
 Acknowledgement
 References
 
Objectives. We postulate that patients with systemic lupus erythematosus (SLE) having recurrent infections are more likely to have poorer disease outcome. The aim of this study is to describe the pattern of infections and disease damage that occurred in a cohort of patients with juvenile-onset SLE, and to find out whether cumulative disease damage was associated with recurrent infections in these patients.

Method. We retrospectively reviewed (1988–2004) the clinical characteristics, infective complications, and disease damage as measured by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index (SDI) in 47 juvenile-onset SLE patients. Potential risk factors for disease damage were evaluated by univariate analysis and logistic regression. The correlation between number of major infections and disease damage was determined.

Results. Thirty-two (68.1%) patients had lupus nephropathy and 16 patients (34%) had neuropsychiatric lupus. Sixty-one episodes of major infections, defined as infections requiring more than 1 week of antimicrobial agents, occurred in 27 patients (57.4%), and 18 patients (31.4%) had recurrent major infections (≥ 2 episodes). Organ damage (SDI ≥ 1) was documented in 21 subjects (44.7%). By logistic regression, occurrence of major infections (P < 0.001) was the only significant risk factor for disease damage. There was a positive correlation between SDI score with the number of recurrent major infections (Spearman's correlation coefficient = 0.50, P < 0.001).

Conclusion. Infections and disease damage are common co-morbidities in juvenile-onset SLE. Recurrent infections could predict poorer disease outcome and associated organ damage in SLE.

KEY WORDS: SLE, Children, Infections, SLE Damage Index


   Introduction
Top
 Abstract
 Introduction
Methodology
 Results
 Discussion
 Acknowledgement
 References
 
Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease predominantly affecting young women in their reproductive age. Approximately 10–20% of all cases of SLE occur in the first two decades of life [1–3]. It has been reported that juvenile-onset SLE has a more aggressive clinical course when compared with adult-onset SLE; more patients in the former group have lupus nephropathy or neuropsychiatric lupus, and the burden arising from long-term morbidity is greater [4–7].

Over the past few decades survival has remarkably improved in children and adolescents with SLE [3, 7, 8], attributable to earlier diagnosis, better monitoring of disease activity, and more judicious use of immunosuppressants [7, 9, 10]. As a result of advancement in renal replacement therapy and other supportive care, renal disease is no longer a strong determinant for survival [11]. With increase in life expectancy, however, patients with SLE are now faced with morbidities due to sequelae of disease activity and adverse side-effects of medications, as well as other complications such as recurrent infections and accelerated atherosclerosis [9, 12]. Infection is now the leading cause of death in SLE patients, followed by severe organ dysfunction related to the disease and its treatment [13–16]. All these comorbidities affect long-term survival as well as quality of life. The focus of management has now shifted from prevention of premature death to minimizing permanent organ damage. Identification of risk factors that lead to active disease and long-term damage is of increasing concern [12].

The major determinants for poorer disease outcome in SLE patients include end-organ involvement [9], disease activity [17] and immunosuppressive treatment [9, 18]. These factors also predispose to infections in SLE patients. We postulate that SLE patients with recurrent infections are more likely to have poorer disease outcome. The primary objective of this study was to describe the pattern of infections and cumulative disease damage that occurred in a cohort of patients with juvenile-onset SLE. Our secondary objective was to identify whether there was any association between recurrent infections and cumulative disease damage in these patients.


   Methodology
Top
 Abstract
 Introduction
 Methodology
Results
 Discussion
 Acknowledgement
 References
 
Clinical setting and practice
Queen Mary Hospital is a university teaching hospital and the paediatric rheumatology unit is a tertiary referral centre for patients with rheumatological diseases. Patients diagnosed with SLE are longitudinally evaluated at 4–12 weeks’ interval. Disease activity is evaluated by history, physical examination and inflammatory markers, but prospective scoring by means of SLE Disease Activity Index (SLEDAI) on a regular basis has only been in practice recently. Patients with minor manifestations such as arthritis, serositis, skin and mucous lesions are treated with non-steroidal anti-inflammatory agents, anti-malarials or low-dose corticosteroids. Damage to major organs such as lupus nephritis, neuropsychiatric lupus, serositis, autoimmune haemolytic anaemia and thrombocytopenia are treated with higher dose of corticosteroids (1–2 mg/kg/day), with or without adjunctive therapy using azathioprine for steroid-sparing effect. For major life-threatening manifestations such as severe neuropsychiatric lupus, acute renal failure or refractory disease, intravenous pulses of methylprednisolone (20–30 mg/kg/day) will be administered, followed by oral prednisolone plus monthly pulses of intravenous cyclophosphamide for 6 months. Once disease is under control, the dose of steroid is kept at minimum and azathioprine is given as maintenance therapy. Ciclosporin A is used for lupus nephritis unresponsive to steroid and cytotoxic agents, but in recent few years mycophenolate mofetil (MMF) is more commonly used in this group of patients. Intravenous immunoglobulin is given for haematological manifestations such as haemolytic anaemia and immune thrombocytopenia. Patients who have refractory disease will be considered for autologous haematopoietic stem cell transplantation.

Patients
Our target population was paediatric patients who were newly diagnosed with SLE and followed up in our rheumatology clinic between 1 January 1988 to 30 June 2004. They were included in the present study if they: (i) fulfilled at least four American College of Rheumatology (ACR) criteria for the diagnosis of SLE [19]; (ii) were below 18 yrs of age at disease onset; and (iii) had a follow-up duration of at least 6 months. Forty-seven eligible subjects were identified, and their hospital records were reviewed from the time of diagnosis up to the time of death, loss to follow-up or the end of the study period by a single reviewer (PL). For those who underwent autologous stem cell transplant, information was analysed up to the commencement of conditioning. Parents of all patients had provided informed consent to participate in research on their clinical data.

This study was approved by the Clinical Research Ethics Review Board of The University of Hong Kong and Queen Mary Hospital.

Disease activity
Disease activity at the time of diagnosis was measured by the SLEDAI, a scale consisting of 24 weighted attributes which are grouped into nine domains by organ systems [20]. Disease flare-up was clinically determined by the attending physician when there was presence of new clinical manifestations or worsening disease compared with previous evaluation requiring restarting or increasing the dose of corticosteroid or immunosuppressive drugs.

Disease damage
The primary outcome measure of disease related morbidity was measured by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index score (SDI) [21]. It consists of 41 items in 12 organ systems and measures irreversible damage that has been present for at least 6 months in an organ or system secondary to inflammation, medication side-effects or other co-morbid conditions that have accumulated since the onset of SLE. A score of zero is given to patients without damage, and the maximum possible SDI score is 47. The SDI score was calculated for each patient at the end of the study period.

Major infections
A major infection was defined as one that necessiated the use of intravenous and/or prolonged course of antimicrobial agents of duration greater than 1 week. They included central nervous system (CNS) infection, bacteraemia, pneumonia, urinary tract infection, deep-seated soft tissue infection such as abscesses and necrotizing fasciitis, herpes zoster and tuberculosis. All diagnoses were verified by clinical features, positive culture results, radiological findings, appropriate response to antimicrobial agents or autopsy.

Study procedures
Data collection
The hospital and out-patient charts of all subjects were reviewed to collect the following data: (i) age at onset of disease, (ii) gender, (iii) initial disease activity as measured by SLEDAI, (iv) absolute duration of disease from diagnosis up to the time of review, (v) involvement of major organ systems (renal, neuropsychiatric, gastrointestinal, pulmonary, haematological and ophthalmic), (vi) timing of renal and neuropsychiatric manifestations in the disease course, (vii) seropositivity of ANCA and antiphospholipid antibody, (viii) type and cumulative duration of corticosteroid and immunosuppressive medications, (ix) the need for renal dialysis in patients with end-stage renal failure, (x) number of infective episodes and (xi) disease damage. Patients who had undergone autologous stem cell transplantation were identified. Renal lesions were classified according to the WHO classification system for lupus nephritis (Class I–VI). Neuropsychiatric manifestations were clinically ascertained and classified into distinct syndromes according to the ACR nomenclature for neuropsychiatric lupus.

The number, types and sites of major infective episodes and the respective microorganism(s) were detailed. The clinical course and treatment 6 months prior to each infective episode were analysed to identify any lupus disease flare-up as defined above.

Seventeen potential risk factors for disease damage were selected for analysis, based on clinical relevance and results from previous literature. They included age at onset of disease, gender, duration of disease, initial SLEDAI, positivity of ANCA and antiphospholipid antibody, major organ involvement, major infections, and cumulative drug treatment. The number of months receiving high-dose corticosteroids (>1 mg/kg/day), cyclophosphamide, azathioprine, MMF, ciclosporin, and the number of pulse therapies with methylprednisolone and cyclophosphamide since SLE diagnosis were recorded.

Statistical analysis
Descriptive statistics were used to depict clinical characteristics such as major organ involvement, drug treatment, nature of infections and their relationship with recent disease flare-up. Means and standard deviations (S.D.) were reported for quantitative variables, while absolute frequencies and percentages were indicated for qualitative variables. Unpaired t-test was used to compare the difference in follow-up duration among patients with and without major infections. Spearman correlation was used to detect any correlation of number of major infections with SDI score.

Subjects were categorized into those with disease damage (SDI score ≥ 1) and those without damage, and the 17 potential risk factors for damage were compared between the two groups. The odds ratio and the 95% confidence interval (CI) were calculated for each of the factors. Unpaired t-test and Wilcoxon rank sum test were used to test for differences in continuous data and Chi-square test with Yates’ correction was used for categorical data. Factors associated with disease damage (SDI ≥ 1) in univariate analysis, based on a P-value of < 0.05, were entered into logistic regression to adjust for the covariate effect, adopting a whole model selection procedure. All statistical analysis was performed by SAS program package V6.12 (SAS Institute, Cary, NC, USA).


   Results
Top
 Abstract
 Introduction
 Methodology
 Results
Discussion
 Acknowledgement
 References
 
Demographics
A summary of demographic data and clinical characteristics of our cohort is shown in Table 1. The mean age of diagnosis of SLE in our cohort was 10.87 ± 3.68 yrs (range 3.48–17.72). The female to male ratio was 10.8 : 1, and the mean duration of follow-up was 6.75 ± 4.37 yrs (range 1.1–17.12, total 317.4 patient-years).


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  		TABLE 1. Demographic data and clinical characteristics

 
Clinical course of SLE
Thirty-two patients (68.1%) developed lupus nephritis and 16 (34.0%) had CNS lupus. Of those with lupus nephritis, 29 (90.6%) occurred within the first year of diagnosis and 27 cases (84.4%) were biopsy-proven. Only one patient developed end-stage renal failure and required long-term haemodialysis. Seven (14.9%) had both renal and neural involvement. The mean interval of development of CNS manifestations from onset of disease was 32.6 months (at diagnosis – 121 months). The most common manifestation was cognitive dysfunction (n = 7) followed by seizure (n = 6) and headache (n = 5). Nine patients had more than one neuropsychiatric syndromes. Three patients had ophthalmic complications including optic neuritis and retinitis. Three patients had haemolytic anaemia, and two patients had severe prolonged thrombocytopenia requiring treatment with intravenous immunoglobulin (IVIG). One patient presented with pericardial effusion which subsequently resolved with treatment. None of the patients had persistent cardiac or respiratory symptoms, but three patients had roentgenographic evidence of pulmonary fibrosis. One patient subsequently developed concomitant Crohn's disease. Since June 2002, five patients underwent autologous bone marrow transplant because of poorly controlled disease activity despite high dose of corticosteroids or immunosuppressive agents; all were successful without disease relapse up to the time of study.

Nature of infections
A total of 120 infective episodes were registered. Fifty-nine were considered as minor infections which were self-limiting, including upper respiratory tract infections (n = 10), oral mucosal infections (n = 20), gastroenteritis (n = 10), superficial skin infections (n = 16), chickenpox (n = 2) and conjunctivitis (n = 1). Sixty-one episodes of major infections, which required treatment with anti-microbial agents for at least 1 week (Table 2), were documented in 27 SLE patients in our cohort (57.4%). Eighteen patients had recurrent episodes (≥ 2) of major infections during the follow-up period. Herpes zoster was the commonest (n = 19), followed by bacteraemia (n = 10), urinary tract infection (n = 9), pneumonia (n = 6) and soft tissue infection (n = 6). A detailed account on the clinical characteristics of herpes zoster in this group of patients was recently published [22]. Except 2 episodes of herpes zoster, which were managed at the out-patient setting, all the rest of major infections were treated in the hospital and the mean duration of hospitalization was 18.0 days. Disseminated Staphylococcus aureus infection resulted in death in one patient who defaulted follow-up and had poor compliance to medications.


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  		TABLE 2. Types of infections and causative microorganisms in patients with juvenile-onset SLE

 
Disease damage and outcome
Disease damage by organ systems measured by SDI is shown in Table 3. Twenty-one subjects (44.7%) had SDI ≥ 1 and 26 patients had SDI = 0, with a mean follow-up duration of 7.53 ± 4.13 yrs and 6.13 ± 4.53 yrs, respectively (P = 0.279). Twelve patients had a score of 1, five had a score of 2, two had a score of 3 or 4, and two had a score of 5 and 7, respectively. The combined total SDI of the study group was 41, and the mean SDI score was 0.87 (range 0–7). Cognitive impairment or major psychosis occurred in seven patients (14.9%) and was the commonest type of damage, followed by cataract (12.8%) and avascular necrosis (8.5%). Damage in skin, cardiovascular and gastrointestinal systems as measured by the SDI was not recorded in our cohort, and none had diabetes mellitus or malignancy.


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  		TABLE 3. SLICC/ACR Damage Index scores at time of last assessment. The number in parenthesis is the number of patients having damage in that domain

 
Infections as related to duration of SLE, major organ involvement and disease activity
The duration of follow-up in patients who experience major infection (7.29 ± 4.18 yrs) was longer than that in patients without major infection (4.98 ± 4.7 yrs), but the difference was not statistically significant (P = 0.126). All major infections occurred in patients who had major system involvement including neuropsychiatric lupus, lupus nephropathy or severe thrombocytopenia. Fifty-one episodes of major infections (83.6%) occurred in patients who had lupus nephropathy and 28 episodes in those with neuropsychiatric lupus (45.9%). Forty-eight major infective episodes (78.7%) occurred at the time of heightened lupus activity. Fourteen episodes (23.0%) occurred at or within 6 months from disease onset; seven of these (11.4%) occurred at the time of first presentation. Nineteen episodes (31.1%) occurred within 6 months of a disease flare-up, and 15 episodes (24.6%) coincided with concurrent active flare-up.

Predictive factors for permanent disease damage
Permanent disease damage as measured by SDI was positively correlated with the number of major infective episodes occurring during disease course (Spearman's correlation coefficient 0.503, P < 0.001). Univariate analysis (Table 4) was performed by comparing variables in patients dichotomized according to the presence (SDI ≥ 1) or absence of damage (SDI = 0). Disease damage was independent of the onset age, gender, disease duration and initial SLEDAI. Occurrence of any major infections (P < 0.001), presence of lupus nephritis (P = 0.023) and use of azathioprine (P = 0.007) had significant association with disease damage (SDI ≥ 1). By logistic regression, occurrence of major infections (OR 2.38, 95% CI 1.25–4.54, P = 0.008) remained the only significant factor for disease damage.


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  		TABLE 4. Factors associated with disease damage (SDI ≥ 1) in SLE by univariate analysis and logistic regression

 

   Discussion
Top
 Abstract
 Introduction
 Methodology
 Results
 Discussion
Acknowledgement
 References
 
In this retrospective study, we showed that long-term disease damage and recurrent infections were significant burden to patients with juvenile-onset SLE despite good overall survival. Lupus nephritis, duration of use of azathioprine and the occurrence of major infections were significantly more common in patients with long-term damage. An interesting finding was the association between major infections and SLE disease damage.

In the past few decades, there has been substantial improvement in the survival of paediatric patients with SLE. In children, the 5-yr survival rate improved from 17.5–69% in the 1950–1960s to 83–93% in the 1980–1990s [1]. More recent studies reported an even better 5-yr survival of 97–100% and 10-yr survival of 86–95% [23, 24]. The 10-yr survival rate in our cohort was 97.6% and was among the best reported. Asian ethnicity was previously believed to be a risk factor for poor outcome in adult-onset SLE, but a recent local study revealed that the long-term survival in Chinese adult patients was similar to that of Caucasians. Also, studies on juvenile-onset SLE did not find any evidence for correlation between ethnicity and damage [9, 17, 23]. Our study showed that the survival rate, outcome for lupus nephritis and disease damage in other domains in Chinese children did not fare worse when compared with other cohorts consisting of predominantly Caucasian subjects. Table 5 shows a summary of major published studies on disease damage in juvenile-onset SLE. With a mean follow-up duration of moderate length (6.75 yrs) and similar age at study entry, the percentage of patients with disease damage (SDI ≥ 1) and the mean SDI score in our study were in the lower range among the reported cohorts. Ocular, neuropsychiatric and musculoskeletal damage were commonly affected as in other cohorts. However, renal damage occurred in only 4.3% of our patients despite 68.1% had lupus nephritis as one of the disease manifestations. Indeed, the 5-yr kidney survival rate (97.0%) was also among the highest reported when compared with other series (44–93%) [7, 24, 25].


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  		TABLE 5. A summary of studies on cumulative organ damage in juvenile-onset systemic lupus erythematosus

 
Compared with other studies, the female to male ratio in our cohort was much higher (10.8 : 1) and approached that in adults with SLE in this locality. Studies conducted by other centres in Hong Kong [4] and Taiwan [8] also showed a higher female to male ratio (9 : 1 and 6 : 1, respectively), suggesting that the low prevalence of juvenile-onset SLE in male could be characteristic of the Chinese population.

Infection is now the leading cause of mortality in SLE patients. A high rate of infections was observed in our cohort (57.4%), and one-fourth had more than three episodes of major infections during their disease course. A study on adult patients with SLE in Hong Kong revealed that infections accounted for 60% of mortality, followed by cardiovascular (12%) and cerebrovascular (16%) diseases [4]. The spectrum of infections and causative microorganisms in this report were similar to those in other adult series [26–32]. The predominant infectious agents were enteric Gram-negative bacteria. A high rate of herpes zoster was observed, and our previous study showed that patients with herpes zoster were more likely to have other major infections as well, suggesting a significantly compromised immune status in these patients.

Important risk factors for long-term disease damage in juvenile-onset SLE derived from previous studies included disease duration, cumulative disease activity, neuropsychiatric lupus, acute thrombocytopenia, hypertension, seropositivity for anti-phospholipid antibody, corticosteroid and cyclophosphamide therapy [9, 17, 18, 23]. In our univariate analysis, lupus nephropathy, duration of azathioprine use and recurrent infections were found to have significant association with disease damage. Although the number of subjects with long-term renal damage was small, the aggressive treatment of lupus nephritis with high-dose or pulse corticosteroid and cyclosphosphamide had led to treatment-related disease damage such as cataract, avascular necrosis of the hips, osteoporosis and premature gonadal failure. Compared with subjects without disease damage, those with disease damage had received longer duration of corticosteroid, cyclophosphamide and MMF and more courses of pulse methylprednisolone or cyclophosphamide therapy suggesting a more persistent and active disease state in these patients, although statistical significance was not reached for these variables which could be related to the small sample size. The observed association between disease damage and longer duration of azathioprine use might reflect persistence of disease activity rather than specific adverse impact of azathioprine on long-term damage. We observed a correlation between the number of infections and severity of disease damage (r = 0.503), and infections remained the only significant factor associated with damage in the multivariate analysis. It would be difficult to establish a causal relationship between infections and long-term damage as underlying risk factors for both are largely common. Inherent immune abnormalities in the active state and the use of immunosuppressive therapy predispose to infections, and both are major contributors to ultimate disease damage.

The low costs and easy accessibility of public health service in Hong Kong is a major reason for our patients to seek medical attention in our unit when they have physical deterioration. Because of this, our medical records are highly reflective of the entire disease course of each patient with documentations of vast majority of clinically significant infections and disease damage. However, being a referral centre a potential bias could be present as our patients might have more severe spectrum of lupus disease, as indicated by the high rate of renal and CNS diseases. A limitation of this study was that an objective measure of overall disease activity was not recorded regularly in the medical records. It would be difficult to reliably calculate the cumulative disease activity in retrospect, which was shown to be an important risk factor for damage. We employed SDI as a standard instrument for measuring disease damage in this study, but impairment in growth and pubertal development, which are specific to paediatric SLE, were not taken into account. In contrast, items such as diabetes and malignancy are extremely rare in children and the clinical significance of these components may have to be considered for appropriate weighting. The applicability of SDI in childhood was also limited by the ability of children to recover and regenerate to a greater degree than adults. Recently, a paediatric version of SDI, which included growth failure and delayed puberty as new domains of damage, was published. [33] This instrument awaits prospective validation.

To conclude, our findings revealed that major infection strongly correlated with severity of disease damage in juvenile-onset SLE. Timely administration of immunosuppressive agents is essential to achieve optimal control of disease activity to minimize flare-up of disease and long-term damage, but judicious use of these agents is equally important to avoid recurrent infections and other associated comorbidities. Patients who have recurrent infections warranted more frequent monitoring of SLE disease activity and more meticulous dose titration of immunosuppressants. The overall survival and kidney survival rate in our cohort were among the highest reported in juvenile-onset SLE, but a significant proportion of patients suffered from at least one domain of long-term damage. Prevention of recurrent infections and disease damage are, therefore, the most important aspect of care in juvenile-onset SLE.

Formula


   Acknowledgement
Top
 Abstract
 Introduction
 Methodology
 Results
 Discussion
 Acknowledgement
References
 
This study was supported by the Shun Tak District Min Yuen Tong Fund.

The authors have declared no conflicts of interest.


   References
Top
 Abstract
 Introduction
 Methodology
 Results
 Discussion
 Acknowledgement
 References
 

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Submitted 26 September 2006; revised version accepted 23 March 2007.
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