Download Lymphopenia at presentation is associated with increased risk of

Q J Med 2006; 99:37–47
doi:10.1093/qjmed/hci155
Lymphopenia at presentation is associated
with increased risk of infections in patients
with systemic lupus erythematosus
W.L. NG1, C.M. CHU1, A.K.L. WU2, V.C.C. CHENG2 and K.Y. YUEN2
From the 1Division of Rheumatology, Department of Medicine & Geriatrics,
United Christian Hospital, and 2Center of Infection, The University of Hong Kong,
Hong Kong Special Administrative Region, China
Received 29 September 2004 and in revised form 31 May 2005
Summary
Background: Patients with systemic lupus erythematosus (SLE) frequently suffer from infections, but
the predisposing risk factors, as well as the exact
frequency and nature of such infections, are not fully
understood.
Aim: To describe the frequency, types and risk
factors for infections in a group of Chinese patients
in the early stage of SLE in Hong Kong.
Design: Retrospective record study.
Methods: We reviewed the case records of 91
Chinese SLE patients, presenting 512 months after
SLE diagnosis. Details of major infections (requiring
intravenous antimicrobial therapy, or any confirmed
mycobacterial infection) and minor infections
were reviewed. Clinical and laboratory features,
the systemic lupus erythematosus disease activity
index (SLEDAI) at presentation and drug treatment
were recorded and analysed.
Results: There were 48 major infections and
62 minor infections during 260 patient-years of
follow-up. A lymphocyte count 41.0 109/l at
presentation was independently associated with an
increased risk for major infection: hazard ratio 4.7
(95%CI 1.6–13.7), p ¼ 0.005. SLEDAI, use of corticosteroids and immunosuppressive therapy were
all not associated with increased risk of infection.
Discussion: Lymphopenia was an important risk
factor for major infections in this group of Chinese
patients in the early stages of SLE. SLE patients
with lymphopenia at presentation should be
closely monitored for the development of infective
complications.
Introduction
Infection is a major cause of mortality and morbidity
in patients with systemic lupus erythematosus (SLE).1
In most modern series, infection ranks first or second
as the commonest cause of death in SLE patients
worldwide, including here in Hong Kong.2–4 Infection is also a major reason for hospital admissions in
SLE patients.1
There are 5- and 10-fold increases in the rate
of infection in SLE patients, compared to similar
patients with nephrotic syndrome and rheumatoid
arthritis, respectively.5 The increase in infection
reflects the multiple immune defects associated with
the disease.6 In addition, the use of corticosteroids
and immunosuppressive drugs such as azathioprine
and cyclophosphamide may lead to further disturbance of the immune system.
Several studies have attempted to identify risk
factors for infection in SLE, with variable results.7,8
Address correspondence to Professor K.Y. Yuen, Centre of Infection, Queen Mary Hospital, The University
of Hong Kong, Hong Kong Special Administrative Region, China. email: [email protected]
! The Author 2006. Published by Oxford University Press on behalf of the Association of Physicians.
All rights reserved. For Permissions, please email: [email protected]
38
W.L. Ng et al.
Major clinical predictors identified include active
lupus,9–11 renal insufficiency12,13 and proteinuria.14
Use of corticosteroids at doses 420–60 mg/day
has been reported to increase the risk of infection,9,10,12,13 as has previous use of steroids.15
However, in other studies, infections were independent of the amount of steroids used.14,16 Other risk
factors, such as the use of pulse methylprednisolone11,14 or cyclophosphamide,10,11 have also been
implicated. Interestingly, leukopenia has not been
shown to be a risk factor for infection,9,10 a finding
noted as surprising in a recent review article by
Petri.1 However, no study to date has looked
specifically into the effect of lymphopenia on the
risk of infection in SLE.
One of the main drawbacks in the design of many
of the aforementioned studies10,16 is that infection
has been regarded as a dichotomous variable,
and predictive risk factors identified by analysing
differences between the groups with and without
infections. In other studies,9,11 the incidence rate
of infection was compared between groups with
differing variables (e.g. steroid dosages or immunosuppressive therapy). However, these approaches
do not take into account of the fact that the
occurrence of infection is a time-dependent function, and infections may not occur at a uniform rate
during the course of SLE. A more meaningful
approach would be to analyse the occurrence of
infection in the form of a survival study,17 where
baseline characteristics are examined for their
effects on the subsequent probability of surviving
without infection.
The current study was conducted to investigate
the frequency and nature of infections in a group
of Chinese SLE patients in the early stages of the
disease who were followed-up in a single rheumatology centre. Clinical and laboratory features at
presentation of the disease (particularly lymphopenia) were examined for their effect on the
probability of the subsequent occurrence of major
infections. Only patients with disease duration 512
months were included, to identify risk factors for
infection operating in the early stages of the disease,
and to enhance uniformity in the care and follow up
of the patients.
Methods
Patients
The Division of Rheumatology in the United
Christian Hospital is the only rheumatology referral
centre serving a population of approximately
0.7 million in the East Kowloon region of
Hong Kong. All patients were followed-up by one
of the authors (WLN). Patients were seen at regular
intervals of 4–12 weeks, as guided by their clinical
conditions. Blood tests were routinely performed
for haematological, biochemical and serological
profiles.
Between July 1994 and June 2000, 149 patients
with SLE were seen on at least two occasions in the
rheumatology clinic. All patients fulfilled the 1982
revised American College of Rheumatology (ACR)
classification criteria for SLE.18 Fifty-eight patients
were excluded from the study: 54 had had their SLE
diagnosis for 41 year before their first presentation
to the rheumatology clinic, two were non-Chinese,
and two had the majority of their care in other
hospitals, with insufficient information for analysis.
The final study group thus comprised 91 patients.
As we decided to assess the role of lymphocyte
count as a predictor for infection, 82 patients with
a lymphocyte count available at presentation were
selected for risk factor analysis.
Data
Medical records were available for all the patients.
Records were retrospectively reviewed using specifically designed forms. Background information was
recorded for sex, age at diagnosis, duration of the
disease at first presentation and duration of followup from time of diagnosis to last follow-up visit,
death or end of the study period. The date of
diagnosis was defined as the time when the patient
first satisfied the 1982 revised criteria for the
classification of SLE. The clinical features and
laboratory results were examined in detail. Features
of lupus corresponding to the ACR criteria were
recorded. Neurological disorders were defined by
the recently published ACR nomenclature and case
definitions for neuropsychiatric lupus syndromes.19
Treatment charts were reviewed. The dosage of
steroid used was recorded, expressed in milligrams
of prednisolone or equivalent. The average dose of
steroid used in the month preceding the first major
infection was computed. The cumulative steroid
dose was summed up to the time of occurrence
of the first major infection or to the end of the
follow-up, in those with and without major infection, respectively. This represented the period at
which a patient was susceptible to the occurrence
of the first major infection. The cumulative use of
intravenous pulse methylprednisolone, azathioprine
and other cytotoxic therapies, including cyclophosphamide, methotrexate and cyclosporin A,
were recorded using a similar method. Disease
activity of SLE at the time of diagnosis was
retrospectively evaluated using the SLE Disease
Infections in SLE
Activity Index (SLEDAI),20 a reliable and valid
instrument for assessing lupus disease activity.21
Retrospective medical record abstraction for SLEDAI
is a valid representation of lupus disease activity,
with good intra-rater and inter-rater reliability.22
All non-scheduled admissions of SLE patients in
the cohort within the 6-year period were recorded.
The principal reason for admission was determined
retrospectively at the time of the review. There were
a small number of episodes in which the patients
were admitted to other hospitals in Hong Kong.
To ensure maximal capture of relevant information,
a territory-wide search was performed via the
Clinical Management System (CMS). The CMS is
a computerized system that enables the retrieval of
clinical and laboratory data in the majority of public
hospitals in Hong Kong. To supplement any missing
information, all discharge summaries, laboratory
results and referral letters from other hospitals were
reviewed, with special attention to the occurrence
of infections.
All episodes of infection from the time of
diagnosis of SLE were recorded. Infections were
documented by clinical evidence and significant
growth of pathogens from normally sterile sites.
Alternatively, when no organism was found, the
diagnosis was based on compatible clinical, radiological and laboratory features and/or a response
to anti-microbial therapy in the absence of an
alternative explanation. Major infections were
defined as those requiring intravenous antimicrobial therapy. All infections by mycobacteria
were regarded as major infections. Minor infections
were defined as those that could be managed
with oral or topical therapy. All cutaneous herpetic
infections were classified as minor unless there was
evidence of dissemination.
The incidence of infection was expressed as
the number of infections per 100 patient years of
follow-up, as previously described.9,11 The time
interval from diagnosis of SLE to the first major
infection was recorded and used for the analysis
of infection-free survival. Potential risk factors for
infection to be analysed included: (i) baseline demographic data (age, sex, duration of SLE on presentation); (ii) presence of various clinical features at
disease presentation as described in the ACR criteria
(malar rash, discoid rash, photosensitivity, oral
ulcers, arthritis, serositis, renal disorders, neurologic
disorders, haematological disorders and immunological disorders); and (iii) SLEDAI at the time of
diagnosis of SLE. In particular, the effect of a
lymphocyte count 41.0 109/l at presentation of
SLE was examined.
Both the activity of SLE23 and the lymphocyte
count24,25 may vary during the course of illness,
39
so their values at disease presentation may not
be extrapolatable to the later part of the disease.
To circumvent this problem, infection-free survival
was re-analysed using follow-up data censored at
12 months. Furthermore, we re-examined the data
by re-classifying major infections as those severe
infections in which there was positive identification
of micro-organisms.
Statistical analysis
Data are expressed as means and standard deviations (SD) for normally distributed measurements,
and medians for non-parametric data. Continuous
data between two groups was compared using the
unpaired Student’s t test or Mann-Whitney U test,
as appropriate. Categorical data were compared
using the 2 test with Yates’ continuity correction,
or Fisher’s Exact Test, as appropriate. Analysis of
duration of infection-free survival used the KaplanMeier plot. Univariate analysis of infection-free
survival with respect to categorical and continuous
variables used the log rank test and the Cox
proportional hazard model, respectively. Variables
with p 5 0.1 were put into multivariate analysis,
using the Cox proportional hazard model with
stepwise selection. Factors with a two-tailed
p value 50.05 in the final model were reported as
independent variables for infection-free survival.
Results
Patient characteristics
There were 85 females and six males (F:M 14.2:1).
Mean age at diagnosis was 37.2 16.2 years
(median 36, range 9–89). Mean duration of
follow-up of the patients was 34.3 25.0 months
(median 28, range 1–84). Total duration of
follow-up for the 91 eligible patients was 260
patient-years.
Table 1 summarizes the clinical features of the
91 patients in the cohort. The lymphocyte count at
the time of diagnosis was available for 82 patients
(90.1%). The mean value was 1.2 0.9 109/l
(median 1.1, range 0.2–5.1); 62% had a lymphocyte
count 51.5 109/l and 49% a count of 41.0 109/l.
Mean SLEDAI at diagnosis was 8.2 5.0 (median 7,
range 0–24).
Infections and hospital admissions
Forty-eight episodes of major infections occurred
in 27 patients (29.7%). Seven (25.9%) episodes
occurred at disease presentation, and 63% within
the first year after diagnosis of SLE. The majority
40
W.L. Ng et al.
Table 1 Presenting features and the cumulative occurrence of ACR criteria in the SLE cohort (n ¼ 91)
Feature
Table 2 Frequencies of major infection (n ¼ 27)
No. of major infections
Patients
1
2
3
11
18
6
2
1*
Presentation Cumulative
Clinical
Malar rash
38 (42%)
38 (42%)
Discoid lesions
3 (3%)
3 (3%)
Photosensitivity
23 (25%)
25 (28%)
Oral ulcers
8 (9%)
8 (9%)
Arthritis
63 (69%)
63 (69%)
Serositis
14 (15%)
14 (15%)
Renal disordera
25 (27%)
27 (30%)
All neuropsychiatricb
5 (6%)
5 (6%)
Haematological
Haemolytic anaemia
14 (15%)
15 (17%)
Leukopenia (54 109/l)
25 (27%)
40 (44%)
Lymphopenia (51.5 109/l) 51/82 (62%) 81/90 (90%)
Lymphopenia (41.0 109/l) 40/82 (49%) 59/90 (66%)
Thrombocytopenia
6 (7%)
11 (12%)
(5100 109/l)
Serological
Anti-nuclear antibody
91 (100)
NA
Anti-ds DNA or Anti-SM
76 (83.5) NA
antibodies
a
Persistent proteinuria 40.5 g/day or presence of cellular
casts. bSeizures (2), transverse myelitis (1), subarachnoid
haemorrhage (1) and peripheral neuropathy (1). NA, not
applicable.
of patients (66.7%) had a single infection (Table 2).
Details of the infections were shown in Table 3.
Micro-organisms could be identified in 30 episodes
(62.5%). The overall incidence was 18.5 infections
per 100 patient-years of follow-up. A total of 62
episodes of minor infections occurred in 37 patients
(40.7%) (Table 4), representing an incidence of
23.8 infections per 100 patient-years.
There were 118 non-scheduled hospital admissions in 51 (56.0%) patients during the study period.
Active SLE accounted for 56 (47.5%), infections
for 41 (34.7%), and the remaining 15 (12.7%) were
due to treatment complications and other causes
unrelated to SLE.
Risk factors for infection
The 82 patients with lymphocyte counts available
at the time of presentation were included in the risk
factor analysis (Table 5). The first group developed
at least one major infection during their clinical
course; the second group never developed any
major infection. The two groups were similar with
regard to age, sex distribution, duration of follow-up,
presence of leukopenia, thrombocytopenia, renal
and neurological disorders and prevalence of
(67%)
(22%)
(7%)
(4%)
*A 31-year-old woman who presented with transverse
myelitis and status epilepticus requiring admission to
intensive care unit. She developed nosocomial pneumonia and recurrent catheter-related urinary tract infection.
anti-DNA antibody at presentation. Other ACR
clinical features were also similar (not shown).
With regard to steroid therapy, the cumulative
steroid doses were similar in both groups. Of those
with major infections, 9 (33.3%) did not receive
any prior steroid therapy, and another 10 (37.0%)
received an average dose of 410 mg prednisolone
in the month preceding the first major infection.
The percentages of patients who had received
intravenous pulse methylprednisolone, azathioprine
or cytotoxic therapy were similar in the two groups.
The time period from SLE diagnosis to the first
major infection was analysed. Risk factors for
infection-free survival were examined using demographic data such as sex, age, auto-antibodies,
SLEDAI and prevalence of various clinical features.
On univariate analysis by log-rank test, both the
presence of haemolytic anaemia (p 5 0.005) and
lymphopenia 41.0 109/l at time of SLE diagnosis
(p 5 0.0001) were associated with an increased
risk of development of a major infection during
follow-up (Table 6). Figure 1 shows the survival
curves according to the presence or absence of
lymphopenia 41.0 109/l at diagnosis. On multivariate analysis using Cox regression, lymphopenia
41.0 109/l at disease presentation was the only
independent predictor for the occurrence of a major
infection: hazard ratio (HR) 4.7 (95%CI 1.6–13.7),
p ¼ 0.005.
To examine further the predictive value of
lymphopenia at disease onset, the data were
re-analysed, with follow-up censored at 12 months.
During the first 12-month period, there were 18
major infections. Sixteen (40%) of the 40 patients
with a lymphocyte count 41.0 109/l developed
a major infection, compared to only 3 (4.8%) of the
other 42 (Figure 2). Lymphopenia 41.0 109/l at
presentation of SLE remained the only independent
risk factor predicting occurrence of major
infection: HR 6.2 (95%CI 1.3–29.3), p ¼ 0.021 by
Cox regression.
Infections in SLE
41
Table 3 Details of major infections (n ¼ 27)
Site (no. of episodes)
Organism
n (%)
Pneumonia (16)
Methicillin-resistant Staphylococcus aureus
Mycobacterium tuberculosis
Pseudomonas aeruginosa
Stenotrophomonas maltophila
Haemophilus influenzae
Haemophilus parainfluenzae
No organism identified
E. coli
Pseudomonas aeruginosa
Klebsiella spp
No organism identified
Mycobacterium tuberculosis
Listeria monocytogenes
No organism identified
Staphylococcus aureus
Mycobacterium tuberculosis
No organism identified
Mycobacterium tuberculosis
No organism identified
No organism identified
Staphylococcus aureus
No organism identified
3
2
1
1
1
1
7
10
1
1
1
2
1
2
2
1
2
2
2
3
1
1
48
Urinary tract (13)
Septicaemia and disseminated infection (5)
Cutaneous (5)
Lymphadenitis (4)
Upper respiratory tract (3)
Septic arthritis (1)
Meningitis (1)
Total (48)
(6.3%)
(4.2%)
(2.0%)
(2.0%)
(2.0%)
(2.0%)
(14.6%)
(20.8%)
(2.0%)
(2.0%)
(2.0%)
(4.2%)
(2.0%)
(4.2%)
(4.2%)
(2.0%)
(4.2%)
(4.2%)
(4.2%)
(6.3%)
(2.0%)
(2.0%)
(100%)
Table 4 Minor episodes of infections in 37 patients
Site (no. of episodes)
Organism
n (%)
Upper respiratory tract (25)
Haemophilus influenzae
Haemophilus parainfluenzae
Influenza A
No organism identified
Herpes zoster
Staphylococcus aureus
Mixed growth (Morganella morganii, Klebsiella pneumoniae)
No organism identified
E. coli
Enterococcus faecalis
Strepotococcus agalactiae
Group D streptococcus
Pseudomonas aeruginosa
No organism identified
Gardnerella vaginalis
Streptococcus milleri
Herpes simplex
3
2
1
20
11
1
1
5
5
1
1
1
1
6
1
1
1
62
Cutaneous (18)
Urinary (9)
Lymphadenitis (6)
Vaginal (1)
Sinusitis (1)
Keratitis (1)
Total (62)
We also analysed the data by re-classifying major
infections to include only those in which there
was positive identification of the infecting microorganism. Under this new definition, major infection
occurred in 12 (30%) of the 40 patients with a
(4.8)
(3.2)
(1.6)
(32.2)
(17.7)
(1.6)
(1.6)
(8.1)
(8.1)
(1.6)
(1.6)
(1.6)
(1.6)
(7.3)
(1.6)
(1.6)
(1.6)
(100)
lymphocyte count 41.0 109/l vs. 3 (7.1%) of the
42 others (Figure 3). Lymphopenia 41.0 109/l at
time of diagnosis of SLE was still the only predictor
for occurrence of major infection: HR 18.1 (95%CI
6.5–50.2), p 5 0.001 by Cox regression.
42
W.L. Ng et al.
Table 5 Demographic and clinical profile of 82 SLE patients (with lymphocyte count available at presentation) with and
without major infections
Age at diagnosis (years)
Total follow-up (months)
Female sex (%)
Leukopenia 54 109/l (%)
Haemolytic anaemia (%)
Thrombocytopenia 5100 109/l (%)
Renal diseasea (%)
Neurological diseaseb (%)
Positive anti-dsDNA (%)
Cumulative steroid dosec in mg
Pulse i.v. methylprednisolone (%)
Azathioprine (%)
Cytotoxic therapyg (%)
SLEDAI at time of diagnosis
Lymphocyte count at presentation ( 109/l) (mean SD)
Patients with major
infection (n ¼ 27)
Patients without major
infection (n ¼ 55)
32.0 (14–80)
28 (1–76)
25 (92.7)
13 (48.1%)
10 (37.0%)
5 (18.5%)
10 (37.0%)
3 (11.1%)
20 (81.5%)
615d (0–17651)
2 (7.4%)
2 (7.4%)e, 5 (18.5%)f
2 (7.4%)e, 5 (18.5%)f
9 (3–24)
0.92 0.9
37 (9–89)
27 (1–84)
51 (92.7)
27 (49.1%)
5 (9.1%)
4 (7.3%)
14 (25.5%)
20 (3.6%)
45 (81.8%)
1568d (0–30767)
5 (9.1%)
16 (29.1%)f
7 (12.7%)
6 (0–18)
1.36 0.8
Data are medians (range) unless otherwise stated. aDefined as persistent proteinuria 40.5 g/day or presence of cellular casts.
b
Included the following: seizures (2), transverse myelitis (1), subarachnoid haemorrhage (1) and peripheral neuropathy (1).
cDosages expressed as mg of prednisolone or equivalent. dCumulative dose of steroid received was summed up to the time
of occurrence of the first major infection and to the end of follow-up, in the groups with and without major infection,
respectively. eCumulative use before the occurrence of the first major infection. fCumulative use at the end of follow-up.
g
Included use of cyclophosphamide, methotrexate or cyclosporin A.
Table 6
Analysis of potential risk factors associated with major infections in SLE
Lymphocytes 41.0 109/l
Presence of haemolytic anaemia
Male sex
Age (per year)
Positive anti-ds DNA
SLEDAI (per point)
Log-rank test p
Unadjusted hazard ratio
(95%CI) by univariate Cox’s
regression and p value
Adjusted hazard ratio
(95%CI) by multivariate
Cox’s regression and p value
50.0001
50.005
0.98
–
0.67
–
5.0
2.5
1.5
1.02
1.1
1.04
4.7 (1.6–13.7) p ¼ 0.005
1.2 (0.4–3.4) p ¼ 0.78
–
–
–
–
(1.9–13.3) p 5 0.001
(0.9–6.5) p ¼ 0.066
(0.2–11.2) p ¼ 0.7
(0.99–1.04) p ¼ 0.28
(0.4–3.4) p ¼ 0.82
(0.95–1.15) p ¼ 0.37
SLEDAI, systemic lupus erythematosus disease activity index.
Deaths
Discussion
There was only one death in the study during the
follow-up period: a 77-year-old lady with history of
Evans’ syndrome (autoimmune haemolytic anaemia
and thrombocytopenia) treated with steroids and
splenectomy. She subsequently developed photosensitive rash, proteinuria with positive ANA
and anti-DNA. Two years later, she developed
ischaemic colitis requiring bowel resection, and
died post-operatively from nosocomial pneumonia
(methicillin-resistant Staphylococcus aureus). Lupus
was not active at the time of death. No autopsy was
performed.
This is the first report from Hong Kong of the risk
factors associated with infections in Chinese patients
with SLE. The study was performed on ambulatory
patients followed-up in a tertiary referral hospital,
all seen within 12 months of diagnosis (i.e. patients
in the early stages of SLE). All patients were
followed in a single centre, under the care of one
rheumatologist.
Infection was common in these patients, with
an overall incidence rate of 18.5 per 100 patientyears of follow-up. In the study of Ginzler et al.,
the incidence of major infections was 13.9 per
Infections in SLE
43
1.0
Patients without lymphopenia
Proportion without major infection
.9
.8
.7
.6
Lymphocyte at onset
.5
lymphocyte ≤ 1
Patients with lymphopenia
.4
.3
lymphocyte ≤ 1
-censored
.2
lymphocyte > 1
.1
lymphocyte > 1
-censored
0.0
0
20
40
60
80
100
Time from SLE diagnosis (months)
Figure 1. Cumulative probability of infection-free survival for the complete follow-up period in SLE patients with or without
lymphopenia (41.0 109/l) at presentation (n ¼ 82).
Proportion without major infection
1.0
.9
.8
Patients without lymphopenia
.7
.6
lymphocyte at onset
.5
Patients with lymphopenia
lymphocyte ≤ 1
.4
.3
lymphocyte ≤ 1
-censored
.2
lymphocyte > 1
.1
lymphocyte > 1
-censored
0.0
0
2
4
6
8
10
12
Time from SLE diagnosis (censored at 12 months)
Figure 2. Cumulative probability of infection-free survival for the initial 12 months of follow-up in SLE patients with or
without lymphopenia (41.0 109/l) at presentation (n ¼ 82).
100 patient years.9 Our infection rate was almost
identical to that in a group of Malaysian SLE
patients.11 but a much lower rate of 6.9 per
100 patient years was observed separately in
Canadian26 and Swedish populations.27 Overall,
34.7% of the hospitalizations within the study
period were related to infections, whereas 47.6%
were attributed to SLE activity. In contrast, in the
W.L. Ng et al.
Proportion without microbiologically confirmed major infection
44
1.0
.9
.8
Patients without lymphopenia
.7
.6
lymphocyte at onset
.5
lymphocyte ≤ 1
.4
lymphocyte ≤ 1
-censored
.3
Patients with lymphopenia
.2
lymphocyte > 1
.1
lymphocyte > 1
-censored
0.0
0
20
40
60
80
100
Time from SLE diagnosis (months)
Figure 3. Cumulative probability of infection-free survival (for microbiologically confirmed major infections) for the
complete follow-up period in SLE patients with or without lymphopenia (41.0 109/l) at presentation (n ¼ 82).
Hopkins Lupus Cohort, which included sicker
patients with longer disease duration, infections
were responsible for only 14% of admissions.28 In
a large, multi-centre prospective study, infections
accounted for 28.9% of deaths among a cohort of
SLE patients, and was the second most common
cause of death identified in that study.29
Most major infections in this cohort were caused
by common bacterial or viral pathogens, most
commonly involving the lungs and urinary tract.
Escherichia coli and Staphyloccocus aureus were the
leading causative pathogens. There was one case
of Listeria monocytogenes bacteraemia, a classic
intracellular organism requiring intact cell-mediated
immunity for body defense.6 Krau et al. reported
seven cases of listeriosis in SLE patients, all having
severe lymphopenia and receiving immunosuppressive therapies.30 Of particular interest was the high
rate (6.6%) of mycobacterial infection in our
patients, similar to the prevalence of tuberculosis
reported in 390 Philippino SLE patients (13.8% over
11 years).31 In a previous Hong Kong study, there
were nine cases of tuberculosis among 156 SLE
patients (5.8%) over 4 years.32 This may reflect the
high local prevalence of tuberculosis in our community. In addition, eleven patients (12.1%) developed
herpes zoster infection in this cohort, with no
disseminated infection. Kahl et al. reported a similar
prevalence of 13.5% among 348 SLE patients.33
Severe opportunistic infections by organisms such
as Nocardia, Pneumocystis carinii, Cytomegalovirus
and systemic fungal infections were not seen in
this cohort. It was unlikely that such infections were
missed, as they would have fatal outcomes if left
untreated.34 There could be a number of reasons for
the absence of severe opportunistic infections in our
study. It is possible that patients with more severe
infections at presentation might have succumbed
before they could be recruited into our study. Severe
opportunistic infections were strongly associated
with use of immunosuppressants,34–36 and patients
with longer disease duration and more extensive
use of immunosuppressants were under-represented
in our study. Also, the clinical manifestations and
mortality pattern of SLE differ in different stages of
the disease.37 Our study reflects the infection pattern
in the early stages of the disease process.
In this study, the occurrence of infection was
expressed as a survival function. The occurrence of
major infections appeared to follow a ‘decrescendo’
pattern, with the majority of events occurring early
in the course of the disease. This may reflect their
susceptibility to infection as a result of the inherent
immune dysregulation in SLE patients.38 These
patients should be followed-up to see whether the
rate and pattern of infections change as a result
of cumulative increase in end-organ damage and
immunosuppressive therapies.
Infections in SLE
Corticosteroid and other immunosuppressive
therapies did not appear to confer excessive
infective risk in our cohort. Many patients were
steroid-naive (33%), and 37.0% received an average
dose of 410 mg/day prednisolone in the month
preceding their first major infection. Only 7.4%
received either azathioprine or cyclophosphamide
prior to infection. Corticosteroids and immunosuppressive agents have a dual effect on the immune
system in SLE.1 Corticosteroids can inhibit migration
and accumulation of leukocytes; bactericidal activity, Fc receptor binding and other functions of
monocytes and macrophages are often impaired.
Glucocorticoids induce lymphopenia by redistributing cells to various tissue compartments, and
T lymphocytes are selectively depleted. Expression of
the adhesion molecule L-selectin is downregulated,
thereby inhibiting lymphocyte migration to lymph
nodes. Corticosteroids also impair lymphocyte
proliferation and cell-mediated cytotoxicity.39 However, by suppressing abnormal cells, corticosteroids
may improve the function of other aspects of the
immune system. For example, abnormal neutrophil
migration in untreated patients may be normalized
in steroid-treated SLE patients,40 and cell-mediated
immunity may improve after prednisolone therapy.41
These may contribute to the inconsistent findings
regarding the role of corticosteroids as a risk factor
for infections in SLE.
Active lupus is recognized as a risk factor for
infection,9–11 but few studies have documented
disease activity using validated instruments.16,42 In
this study, we used the SLEDAI, a widely accepted
instrument.21 Mean SLEDAI at the time of diagnosis
of our patients was 8.2 5.0 (median 7, range
0–24), which is similar to those reported in other
case series of hospitalized SLE patients.16,42 There
was a trend for increased risk of infection in patients
with more active disease (SLEDAI 47), (p ¼ 0.058
by log rank test), but this was not significant on
multivariate analysis.
Previous studies looking at leukopenia as a
predictor of infection in SLE have yielded negative
results.9,10 However, total white cell count is an
imprecise representation of leukocyte components,
and lymphopenia can occur with a ‘normal’ total
white cell count. In our patients, the prevalence
of leukopenia (54 109/l) was only 27%, whereas
lymphopenia (51.5 109/l) was present in 62%
of patients at presentation (Table 1). Moreover,
depletion of different cellular components may predispose to infections with different pathogens.43,44
We therefore advocate measuring differential
leukocyte counts for patients with SLE.
To our knowledge this is the first study to
document lymphopenia as a risk factor for infections
45
in SLE patients. As illustrated in Figure 2, the risk
of developing a major infection over the six-year
period was increased by approximately 5-fold for
patients with lymphocyte counts 41.0 109/l at
presentation. Since lymphocyte count in SLE
patients may vary with time and disease activity,
and could be modified by treatment,24,25 the
lymphocyte count may fluctuate during the course
of disease. In this cohort, the prevalence of
lymphopenia 41.0 109/l had increased from
49% to 66% by the end of the follow-up period.
We repeated our analyses, using data censored
at 12 months from diagnosis. As shown in Figure 3,
the presence of lymphopenia 41.0 109/l
remained strongly predictive for the occurrence of
major infection.
There is surprisingly little literature on lymphopenia in SLE, despite its common occurrence in this
disorder.24,25,45,46 Lymphopenia is well known to predispose to infections, especially in patients infected
with human immunodeficiency virus (HIV)44 and
those with idiopathic CD4þ T-lymphocytopenia.47
Patients with a CD4 count of 50.2 109/l have
a dramatic increase in the incidence of opportunistic
infections such as Pneumocystis carinii pneumonia44 and tuberculosis.48 The mechanism of
lymphopenia in SLE is not clear. Lymphopenia
commonly develops in SLE patients during active
disease24,45 and is strongly associated with coldreactive, complement-fixing, and presumably
cytotoxic anti-lymphocyte antibodies.49 Another
potential mechanism of lymphopenia is increased
apoptosis, as reflected by increased expression of
Fas antigen on T cells.50
Apart from the aforementioned clinical risk
factors, there are other potential contributing factors
to the risk of infections in SLE patients that have
not been thoroughly investigated. For instance, the
integument and mucosal barriers may break down
as a result of vasculitis. SLE patients may have a low
serum level of mannose-binding lectin (MBL),51
which is an important protein in the opsonization
and phagocytosis of microbes, leading to complement activation and deposition.17,52 In addition,
multiple defects in the macrophage/monocyte
system, ‘natural killer’ cells, as well as T and
B cells, are common.38 Autosplenectomy and
functional hyposplenia may also confer infection
risk.53 These factors may contribute to the inconsistent findings reported in previous studies of risk
factors for infections in SLE.
Our study is limited by its retrospective nature
and relatively small sample size. We included only
newly diagnosed patients, and the findings may
not be applicable to other patient groups. Only the
first major infection was studied, and subsequent
46
W.L. Ng et al.
infections were not analysed. As mentioned
previously, parameters such as the disease activity,
lymphocyte count, cellular functions and concomitant immunosuppressive therapies are changing
dynamically throughout the disease course. As this
was a retrospective study, lymphocyte count during
follow-up was not measured by our standard
protocol, so the effect of persistent lymphopenia
on the risk of infection could not be ascertained.
In future studies, patients should be followed
prospectively from an early stage and monitored
serially to correlate the occurrence of various types
of infections with different variables.
In our SLE patients, infections were common
and lymphopenia was an important risk factor for
infection. Further studies on lymphocyte subsets
should be performed to delineate the quantitative
and qualitative immune defects associated with
increased risk of infections in SLE patients.
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