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Infections in outpatients with systemic lupus erythematosus: a prospective study

A Zonana-Nacach, A Camargo-Coronel, P Yañez, L Sánchez, F J Jimenez-Balderas and A Fraga
Lupus 2001 10: 505
DOI: 10.1191/096120301678416088

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 Lupus (2001) 10, 505±510
ß 2001 Arnold All rights reserved 0961±2033
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PAPER

Infections in outpatients with systemic lupus erythematosus:

a prospective study
A Zonana-Nacach1*, A Camargo-Coronel1, P YanÄez1, L SaÂnchez1, FJ Jimenez-Balderas1 and A Fraga1
1
Department of Rheumatology, Hospital de Especialidades Centro MeÂdico Nacional, `Siglo XXI', Instituto Mexicano del Seguro Social, Mexico City,
Mexico

The objective of this study was to assess the incidence and risk factors of infections in 200 SLE
outpatients. All outpatients with active or inactive SLE without infections in the previous month
were included. They were assessed every 3 months. Major infections were those requiring
hospitalization and parental antibiotic therapy; minor infections required oral or topical therapy.
Sociodemographic, disease activity using the Systemic Lupus Erythematosus Disease Activity
Index (SLEDAI), therapy and laboratory variables were evaluated.
After a follow-up of 22  7 months, 65 (32%) patients had infections; 35% of those were major.
The most common sites for infection were urinary (26%), skin (23%), systemic (12%), and vaginal
(9%). At infection onset, 50 of 65 patients (77%) had disease activity, with a mean SLEDAI score
of 6.1. The variables signi®cantly associated with infection in the univariate analyses were the
presence of disease activity, SLEDAI score, renal activity, prednisone dose, and IV cyclophos-
phamide. The only variable associated with infection in the multivariate analyses was a SLEDAI
score of 4 or higher.
Most infections in SLE outpatients were single, minor, non-life threatening, and associated with
disease activity independently of sociodemographic and therapeutic factors. Lupus (2001) 10,
505±510.

Keywords: systemic lupus erythematosus; infections; risk factors; outpatients

Introduction However, there are few published infection cohort

Despite a linear improvement in survival rates over
the past few decades,1,2 infections in systemic lupus
erythematosus (SLE) patients have remained a major
cause of morbidity3,4 and mortality.5 ± 7 An increased
infection rate has been attributed to underlying disease
without relation to therapy and lupus activity, due to
both humoral and cellular abnormalities that predis-
pose to infections complications.8 ± 12 Several other
factors thought to in¯uence infections in SLE, such as
older age, longer disease duration, anti-dsDNA posi-
tive,13 number of disease manifestations,14 doses of
prednisone,15,16 use of immunosuppressives,17 disease
activity18,19 and decreasing renal function16 have been
associated with infections in SLE in some studies.
*Correspondence: A Zonana-Nacach, 143 1=2 D. Avenue, Coronado,
CA 92118, USA.
E-mail: zonanaa@yahoo.com
Received 15 January 2001; accepted 9 April 2001
studies in SLE outpatients.14,20 ± 23 The majority
of studies have been done with other purposes
such as evaluation of survival,13,6,24 hospitalization
causes3,17,25 and outcome.13 In addition, the relation-
ship between infection and disease activity using a
reliable and valid index to evaluate has not been
thoroughly studied. Primarily this has been studied
retrospectively and in hospitalized SLE patients.18,19
The purpose of this study was to determine system-
atically the incidence and risk factors of infections in
SLE outpatients. Sociodemographic, disease activity,
therapy and laboratory variables were assessed as
possible risk factors for infection.
Patients and methods
Study population
SLE patients of the Department of Rheumatology,
at the Hospital de Especialidades, Centro Medico

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 Infections in SLE
A Zonana-Nacach et al
506
Nacional (HECMN), Mexico City, have been included
in a database since 1990. Conventionally, staff see
patients at 3 month intervals. At each visit patient
history is reviewed in addition to physical examina-
tion and laboratory tests being performed. These
patients have been referred to HECMN by their
consulting physicians, peripheral clinics and general
hospitals from southern Mexico City, where severe
lupus patients require attention from a third level
hospital.
Procedures
Patients eligible for this study were those attending
the outpatient clinic of the Department of Rheumato-
logy from January 1996 to January 1998. Only those
outpatients without infections (not receiving oral or
parenteral antibiotics) in the previous month at study
entry and with active or inactive SLE that ful®lled
four or more of the classi®cation criteria de®ned by
the American Rheumatism Association26 (ARA), now
American College of Rheumatology (ACR), were
selected. Patients who required prophylactic therapy
for tuberculosis (isoniazid, 300 mg per day) partici-
pated in the study. Patients were assessed every 3
months in the outpatient clinic and were instructed to
report suspected infections without delay to permit
immediate diagnosis.
Classi®cation of infections
The only infections registered were those con®rmed
both by clinical ®ndings and positive cultures. Where
bacterial isolates were not available, as in pneumonia,
sinusitis or an otitis, infection was con®rmed by
clinical ®ndings in combination with either radio-
graphic diagnosis (pneumonia or sinusitis) and
response to antibiotics. Major infections were de®ned
as those requiring hospitalization and intravenous (IV)
therapy with antibiotics. Minor infections were those
that did not require hospitalization and were treated
with oral antibiotics. A patient was reported having
one infection if one pathogenic organism was isolated
in the same anatomic site or multiple infections if
more than one pathogenic organism was isolated in
separated anatomical sites. Acute viral infections were
de®ned in those patients who had clinical manifesta-
tions or laboratory abnormalities due to possible viral
infections, or when it was possible to con®rm diag-
nosis by determining high titers of antibodies for
virus-speci®c antigens. Opportunistic organisms were
designated according to Cohen's listing,17 which is
based on principles proposed by von Graevenitz.27
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Measurement of clinical activity
Disease activity (overall, renal and extra-renal) of
SLE was evaluated using the SLEDAI.28 This instru-
ment was applied at baseline evaluation (SLEDAI-1)
and at infection onset (SLEDAI-2). The SLEDAI
consists of weighted scores for the presence of spe-
ci®c clinical features and laboratory measures, yield-
ing a total overall score. The de®nition of disease
activity (¯are) was the presence of new clinical
manifestations and=or disease worsening compared
with the previous evaluation, which usually required
restarting or increasing corticosteroids or immunosup-
pressive drugs. A patient was considered to have renal
activity if they had a new onset and=or a recent
increase of proteinuria >0.5 g=24 h, erythrocyturia
>10 red blood cells=hpf, heme-granular or epithelial
casts. Extra-renal activity was de®ned as those
patients without renal activity but with central nervous
system, cardiopulmonary, hematological cutaneous or
musculoskeletal activity.
Laboratory studies
Laboratory studies were obtained only in those
patients who developed infection, which were deter-
mined at infection onset. Complete blood count,
erythrocyte sedimentation rate (ESR; Wintrobe),
glucose, urea, creatinine, urinalyses, creatinine and
protein clearance in 24 h urine; anti-dsDNA, C3
and C4 levels were determined by Farr and radial
immunodiffusion, respectively.
Study measurements
Socioeconomic factors included education and income
levels. Education was measured by the number of
years of education and was analyzed as a categorical
variable (<12 y and >12 y); income was measured as
total yearly household income. A dichotomous
income variable was de®ned as income above or
below the Mexican national poverty level (< 5000
pesos and >5000 pesos monthly). Clinical factors
included disease duration and disease activity. Disease
duration was categorized as (1 ± 5 y, 6 ± 10 and >10 y
of SLE evolution). Disease activity was measured by a
continuous variable (overall SLEDAI scores) and as a
categorical variable (without disease activity SLEDAI
score 0, mild disease activity 1 ± 3, and moderate
disease activity SLEDAI score  4, with renal or
extra renal activity). Treatment included prednisone
therapy (without prednisone, 2.5 ± 10, 11 ± 30 and
31 mg=day), and immunosuppressive therapy (with
and without oral immunosuppressives, and therapy
with IV-cyclophosphamide). Disease activity and

treatment were assessed twice, at baseline and at the
time of infection onset.
Statistical analyses
The outcome variable, infection, dichotomized into
two groups: those who developed infection and those
who did not develop infection. Sample t-tests were
performed for normally distributed variables to test for
signi®cant differences between SLE subjects with and
without infection. Categorical comparisons were also
performed using chi-squared analysis. Multivariate
analyses using logistic regression were used to identify
which of these baseline variables were signi®cantly
associated with infection (dependent variable).
Results
Patient characteristics at study entry
The majority of the 200 Mexican SLE patients studied
were women (94%); their mean (s.d.) age was 35
( 10) y; 52% were married and had an education
Table 1 Baseline sociodemographic, clinical and therapeutic
features in SLE patients (n ˆ 200)
Age, mean s.d. (y)
Female sex (%)
Marital status, married (%)
Education 12 y (%)
Poverty (%)
SLE duration, mean  s.d. (months)
Patients without prednisone (%)
Prednisone, mean  s.d. (mg=day)
Patients with oral immunosuppressives (%)
Patients with IV cyclophosphamide (%)
Disease activity (%)
SLEDAI ˆ 0
SLEDAI  1
Renal activity
Extra-renal activity
Disease activity, mean s.d. SLEDAI-1a score
a
SLEDAI-1 ˆ assessed at study entry.
Infections in SLE
A Zonana-Nacach et al
507
mean of 12 y; 20% were below the Mexican national
poverty level. The mean (s.d.) duration of the disease at
study entry was 98 (71) months. At study entry 65%
had an inactive disease (SLEDAI ˆ 0); 35% had an
active SLE (SLEDAI-1 2.0 3.5), 13% renal and 22%
had extra-renal activity. Eighty-four percent of patients
were taking prednisone (17.8 15 mg=day), the mean
(s.d.) prednisone dose in those patients with inactive
disease (SLEDAI ˆ 0) was 7.8 mg=day (4.3). Sixteen
percent were receiving oral immunosuppressive and
7.5% IV cyclophosphamide (Table 1).
Infections
After a follow-up mean of 22  7 (range 1 ± 42)
months, 65 (32%) patients developed infections. The
mean (s.d.) time from baseline to onset of infection
was 11 (9) months. Thirty-®ve percent were major and
65% minor infections. Table 2 shows the anatomic
site of infections and the isolated microorganism. The
most common infections were urinary (26%), skin
(23%), systemic (12%), vaginal (9%), pulmonary,
gastrointestinal and upper respiratory tract (6%) and
musculoskeletal (1%). Ninety percent of patients had
one infection, and 10% had multiple infections. The
microorganisms isolated were principally bacillus
35  10
gram negative 42%, fungi 18%, and coccus gram
94 positive 13%. Twelve percent were viral infections
52 (diagnosed from clinical and virus-speci®c tests).
52
20
Opportunistic infections were found in nine patients
98  71 (Candida albicans ˆ 6, Pseudomonas ˆ 1, Myco-
16 bacteria tuberculosis ˆ 1, and Cytomegalovirus ˆ 1);
17.8 15
16
90% of patients with opportunistic infections had
7.5 disease activity at infection onset and 30% were
receiving IV cyclophosphamide.
65
35
13
22
Univariate analyses
2.0 3.5
The univariate analyses demonstrated a signi®cant
association between the presence of disease activity

Table 2 Sites of infections and isolated microorganismsa (n ˆ 65)

Site Total Microorganism

Pulmonary 4 Klebsiella (1), pulmonary abscess (1), unidenti®ed (2)

Urinary 17 Escherichia coli (10), Mycobacterium tuberculosis (1), Pseudomonas (1), Staphylococcus coagulase negative (1),
Citrobacter (2), Candida albicans (1), Streptococcus B hemolytic (1)
Gastrointestinal tract 4 Candida albicans oral mucosa (3), bacterial peritonitis (1)
Skin 15 Cellulitis (9), Trichophyton rubrum (2), Staphylococcus aurum (2), Citrobacter (1), pyogen granuloma (1)
Upper respiratory tract 4 Staphylococcus aurum (2), Streptococcus pneumoniae (1), otitis media (1)
Vaginal 6 Candida albicans (3), Proteus mirabilis (1), Proteus vulgaris (1), Gardnerella vaginalis (1)
Systemic (viral) 8 Epstein±Barr ‡ Cytomegalovirus (1), Herpes simplex (1), Herpes zoster (4), Hepatitis B (1), Hepatitis C (1)
Musculoskeletal 1 Septic arthritis by Salmonella
Multiple infections 6 Excherichia coli (urine) ‡ proteus (skin); Candida albicans (urine and esophagus), Escherichia coli (urine) ‡
Staphylococcus aerus (throat) Escherichia coli (urine) ‡ Staphylococcus aurum (throat); Pseudomona (lung) ‡
Candida albicans (oral); Escherichia coli (urine) ‡ Candida albicans (urine)
a
Microorganisms were isolated in 44 (67%) of the 65 infections.

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 Infections in SLE
A Zonana-Nacach et al
508
at baseline (P ˆ 0.01), SLEDAI score (P ˆ < 0.009), Multivariate analyses
renal activity (P ˆ 0.002), prednisone dose (P ˆ 0.03)
The only variable found to independently predict
and IV cyclophosphamide (P ˆ 0.02). There was no
infection was a SLEDAI score of  4 (Table 4).
association with the use of oral immunosuppressives,
age or disease duration. No signi®cant negative cor-
relation was found between infection and the variables Laboratory abnormalities at onset of infection
age, education and income (Table 3). The type of
The most frequent laboratory abnormalities found at
infection (major, minor) and location (one, multiple)
onset of infection were lymphocytes <1500 mm3
were not associated with age, education, annual
(64%); leucocyte count >10 000 mm3 (17%); leuko-
income, disease duration, the presence of disease
cyte count <4000 mm3 (6%); ESR >30 mm=h (31%);
activity, SLEDAI baseline score or treatment. How-
low C4 (47%); low C3 (37%); positive anti-dsDNA
ever, patients with infections and an active SLE had a
(28%); a creatinine clearance <80 ml=min (33%);
higher percentage of viral (12%) and skin infections
hemoglobin <12 mg=dl (17%); and blood glucose
(23%) than patients with infections with an inactive
>140 mg=dl (10%).
SLE, 0 and 6% respectively.
At infection onset, 10 (15%) of the 65 patients were
not receiving prednisone; 27 (41%), 20 (31%), and
8 (12%) were taking prednisone 2.5 ± 10, 11 ± 30 Discussion
and >30 mg=day respectively. Seventeen patients
(29%) were receiving oral immunosuppressives and The susceptibility of SLE patients to infection has a
eight patients (12%) IV cyclophosphanide. Fifty broad-spectrum depending on which type of patients
(77%) of those patients who developed an infection are studied (outpatients or hospitalized), whether they
had disease activity, with a mean (s.d.) SLEDAI-2 have overall or renal disease activity, whether they are
score of 6.1 (4.3); in 33 (51%) patients the SLEDAI-2 receiving high doses of steroids, cytotoxic or immu-
score was 4 or higher. nosuppressive drugs, plasmapheresis or have had
renal transplant. Despite the bene®cial aspects of
newer therapeutic interventions to improve clinical
outcome in patients with SLE, the incidence of infec-
tions as a cause of morbidity and mortality has not
Table 3 Univariate analyses of sociodemographic, clinical, and
therapeutic variables associated with infection at baseline changed over the past 30 y.
A wide spectrum of infections has been reported in
Infections No infections SLE patients, most involving bacterial infections. The
Feature (n ˆ 65) (n ˆ 135) P
incidence of infections may vary widely from study to
Age, mean s.d. (y) 35 9 35  11 0.79 study (26 ± 78%). Most frequently minor infections
Education <12 y (n) 53 103 0.90
Poverty (n) 12 27 0.70
involve the urinary tract and skin, while major infec-
SLE duration, mean  s.d. 103 75 95  69 0.56 tions most commonly cause pneumonia.14,16,20,29 ± 32
SLE active at baseline (n) 31 39 0.01 This study found that in SLE outpatients most
SLEDAI-1 score, mean  s.d. 3.5  4.8 1.2 2.5 0.009
Renal activity (n) 16 10 0.002
infections were minor, due to Gram-negative enteric
Extra-renal activity (n) 15 27 0.65 bacilli, affecting principally the urinary, skin, sys-
Prednisone mg=day, mean s.d. 19.3 18.9 12.4 13.6 0.03 temic (viral) and vaginal organs. Opportunistic infec-
Oral immunosuppressives (n) 11 21 0.83 tions, once considered rare, have been reported with
IV cyclophosphamide (n) 9 6 0.02
higher frequency in SLE. Fourteen percent of the
infections were opportunistic; Candida albicans was
the most common opportunistic pathogen, 90% had
Table 4 Multivarite analyses of infections in SLE outpatients disease activity and one-third were receiving IV
Feature Parameter estimate Standard error P cyclophosphamide at onset of opportunistic infec-
tions. The low frequency of tuberculosis infection
Education 7 0.1565 0.1576 0.32
Age 7 0.0024 0.0175 0.89
found in patients of this study, despite the fact that
Disease duration 0.0047 0.0026 0.06 Mexico is an endemic country, was probably due to
Overall disease activity 7 4.290 13.514 0.75 prophylaxis therapy with isoniazid received by those
Renal activity 3.859 13.530 0.77
No renal activity 4.390 13.513 0.74
with higher doses of prednisone, contrary to the 5%
SLEDAI score 4 1.715 0.771 0.026 incidence of tuberculosis infection reported in SLE.33
Prednisone dose 0.145 0.143 0.31 A number of factors, including underlying host-
Oral immunosupressives 0.202 0.442 0.64
IV cyclophosphamide 0.703 0.704 0.34
defense abnormalities, prolonged therapy with cortico-
steroids and alkylating agents, further suppressing
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an already abnormal immune response that could
increase the risk of infections. However, the complex-
ity is multifactorial and is caused by poorly under-
stood interrelationships between a number of
interacting elements, including level and extent of
disease activity, length of time of disease presence,
and the degree of immunosuppression secondary to
therapy in addition to that already caused by under-
lying illness.
The ®rst study to carefully examine which factors
were associated with an increase of infections in SLE
described 23 patients with SLE, 20 with rheumatoid
arthritis (RA) and 11 with nephrotic syndrome (NPS)
hospitalized at the National Institute of Health (NIH)
during 1960 ± 1969. The overall infection rate
(infections  100 hospital days) was 10 times greater
in SLE patients than RA or NPS. Infection rate
and number of disseminated infections were found
to increase in lupus patients with prednisone
dose >20 mg=day and decreasing renal function
(BUN > 60 mg=%).16 Studies by Urowitz29 and Lee14
also noted the association of major infections with
corticosteroid therapy and active renal disease.
Patients treated only with low doses of prednisone
(equivalent to or less than 10 mg=day) also have
increased infection rates, apparently attributable to
the primary disease.34 ± 36 Similarly, Cohen et al,17
have shown an increased infection rate in lupus
patients compared to other autoimmune diseases
such as Wegener's granulomatosis, anti-glomerular
basement membrane antibody disease and systemic
vasculitis, diseases that often are treated with higher
doses of prednisone
The association of azathioprine with an increased
incidence of infections was noted by Lee et al,14
however, in a subsequent study by Ginzler et al,20
azathioprine was only associated with an increased
incidence of herpes zoster in patients with SLE.
Likewise, studies from the NIH37 ± 39 failed to demon-
strate an additive effect of cytotoxic drugs and pred-
nisone in increasing the infection rate, but did show
that cyclophosphamide increases the incidence of
localized herpes zoster infections as reported by
Kahl.40
Some studies have found laboratory abnormalities
such as low C3 or high ESR to be predictors of
infections,20,24 but like other studies21,41 this study
did not ®nd that association. Other studies have
examined the usefulness of CPR, suggesting that
CPR higher than 60 mg=dl indicates a distinction
between infection and exacerbation in the absence
of serositis.35
Superimposed infections in lupus patients may
trigger disease exacerbation,42,43 induction44,45 or
aggravation46 of SLE. Duffy et al18 found that in
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Infections in SLE
A Zonana-Nacach et al
509
hospitalized SLE patients infection was signi®cantly
associated with overall disease activity. An SLEDAI
score of 8 or greater at the time of hospitalization was
most sensitive and speci®c for predicting the devel-
opment of infection showing a risk of 2.7 times
higher. Ginzler et al20 have shown a frequency of
infection of 74 per 100 patient-years during intervals
in which a new exacerbation of SLE was observed,
compared to 51 infections per 100 patient-years in
intervals without a new ¯are of lupus. The association
of infection and disease activity has important clinical
considerations. The most distinctive feature that
makes infection dif®cult to assess in lupus patients
is the fact that manifestations of the infection process
in these patients may be identical to speci®c aspects of
the underlying disease activity. Moreover, infections
not only may mimic a ¯are, but also may also
precipitate one, causing further diagnostic dif®culties.
Alternatively, because of the impairment of in¯am-
matory response, signs and symptoms of infection
may be subtle.
There are practical implications of this study that
may help to minimize the risk of infections. Patients
with an SLEDAI score 4 must have close monitor-
ing. Also, this study demonstrates that infections
morbidity in outpatients with SLE (33% suffered
infections during disease course) have not changed
as compared with other studies. In addition, during
this study there were no reported deaths. Low mor-
tality found in our study may possibly be due to the
type of patient seen, outpatients with mild disease
activity with close physician monitoring, that allowed
higher physician awareness to make early diagnosis of
infection.
In conclusion, in SLE outpatients most infections
were single, minor, and non-life threatening. Moder-
ate disease activity was the only variable signi®cantly
associated with an increased risk of infections.
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