Infections in Immunocompromised Rheum PT PDF

Crit Care Clin 18 (2002) 931 – 956
Infections in the immunocompromised

rheumatologic patient
Stephen B. Greenberg, MD*
Departments of Medicine, Molecular Virology, and Microbiology, Baylor College of Medicine,
One Baylor Plaza, Houston, TX 77030, USA
Ben Taub General Hospital, Houston, TX 77030, USA
Infections in immunocompromised patients with rheumatic diseases cause

significant morbidity and mortality [1– 51]. Because the clinical manifestations
of infections are often indistinguishable from the underlying disease, recognition
and treatment of these infections may be delayed [52 – 55]. The typical signs and
symptoms of infection may be absent because of concomitant immunosuppressive
therapies [56 – 61]. Potential pathogens include bacteria and less frequently
encountered opportunistic agents [62 –75]. For these reasons, infections are often
difficult to diagnose and treat.
Patients with systemic lupus erythematosus (SLE) are prone to infection of the
CNS, lungs, urinary tract, skin, and soft tissue [76 – 79]. During the course of the
disease, approximately 50% will have at least one infection. Infections in SLE
patients are related to immunologic defects caused by the disease itself or by the
therapy employed [5]. In addition, infections may be promoted by progression of
the disease or by medical procedures such as arthrocentesis [80]. In SLE patients,
infection is a cause of hospital admission as well as a leading complication
following admission. In several series, infection is reported as the leading cause
of death in SLE patients [4,20,24,30,48,50,51].
In patients with rheumatoid arthritis (RA), diminished survival is associated
with comorbidities of the disease [54,81]. Major comorbidities include cardio-
vascular disease, malignancy, gastrointestinal disease, osteoporosis, and infection
[5,8,11,19,27,29,82,83]. The infections are related to the immunosuppressive
therapy as well as to the intrinsic effects of RA on certain organ systems,
specifically the musculoskeletal system [38,39,55,60,84,85].
* Department of Medicine, Baylor College of Medicine.

E-mail address: stepheng@bcm.tmc.edu (S.B. Greenberg).
0749-0704/02/$ – see front matter D 2002, Elsevier Science (USA). All rights reserved.
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932 S.B. Greenberg / Crit Care Clin 18 (2002) 931–956
Predisposing factors to infection

The major predisposing factors to infection in patients with SLE or RA are
known to overlap (Tables 1, 2). In SLE patients, alterations in phagocytic cells
are common with disease activity [86]. Cellular immunity is impaired, as
reflected by lymphopenia, decreased CD4 cell counts, and reduced cytokine
production [87,88]. Reduced immunoglobulin and complement levels have also
been reported in SLE patients [89]. Functional asplenia may reduce the
elimination of bacteria from the blood stream [90,91]. The use of corticosteroids
and immunosuppressive drugs is also a major risk factor for infection.
Chronic inflammation in RA leads to bone and joint deformity that pre-
disposes patients to local infections especially septic arthritis [3,11]. Recent
analysis of infections in RA patients demonstrated the importance of duration
of steroid use, the cumulative methotrexate dose, and the mean daily dose of
D-penicillamine [19].
Immunologic effects of corticosteroid use

Certain infectious diseases are associated with chronic steroid use [58].
Predisposition to these infections is attributed to the deleterious effects of steroids
on the immune system [92,93]. Corticosteroid use will result in skin atrophy, easy
bruising, and delayed wound healing. These conditions can result in increased
access of skin flora to subcutaneous tissue and subsequent infection. Cortico-
steroid use also leads to neutrophilia, decreased migration of neutrophils to sites
of inflammation, inhibition of chemotaxis, and decreased phagocytosis and
intracellular killing of microorganisms. The effects of chronic steroid use on
lymphocytes include lymphocytopenia and suppression of normal delayed
hypersensitivity reactions [94]. Monocytic and macrophage activities can also
be adversely affected by chronic steroid use. Serum IgG concentration is
decreased after 3 to 5 days of corticosteroid use [95]. Although the total white
blood cell (WBC) count may exceed 20,000/mm3 because of the increased
release of mature neutrophils from the bone marrow and decreased exit of
neutrophils from the circulation, the band and metamyelocyte percentage rarely
exceeds 6% of the total count [60].
Table 1
Predisposing factors to infection in patients with SLE
Alteration in phagocytic function
Defects in cellular immunity
Decreased production of immunoglobulin
Low complement levels
Reticulo-endothelial system impaired organism elimination
Chronic use of corticosteroids and/or immunosuppressants
S.B. Greenberg / Crit Care Clin 18 (2002) 931–956 933
Table 2
Predisposing factors to infection in patients with RA
Chronic inflammation producing deformed bones and joints
Chronic use of steroid and/or immunosuppressants
Infections in corticosteroid-treated patients are those associated with defective

phagocytic function and with some diminished cell-mediated immunity (Table 3)
[96 – 98]. The incidence of infectious complications rises with increasing daily
doses given for more than 4 weeks [44]. The relative risk ratio for infection was
reported to be 1.6 in all patients receiving corticosteroids compared with those
not receiving corticosteroids. Alternate-day steroid use reduces the risk of
infection considerably. Lower doses of pulse methyl prednisolone to treat SLE
flares also decrease the risk of serious infection [99].
Other immunosuppressive therapies

Cytotoxic drugs affect the production of phagocytes and lymphocytes. Drugs
such as cyclophosphamide, azathioprine, or methotrexate are often given in
conjunction with corticosteroids in rheumatic diseases [100,101]. When cytotoxic
drugs are given alone or with alternate-day steroids, there is a significant
lowering of infectious complications.
Cyclophosphamide causes neutropenia resulting from decreased production
and increased destruction of neurtophils [102]. Hoffman et al reported on 158
patients with Wegener’s granulomatosis who received cyclophosphamide and
prednisone therapy [20]. Serious infections occurred in 46% of patients. Pneu-
monia caused by Staphylococcus aureus, Pseudomonas aeuginosa, and Haemo-
philus influenzae was the most frequent serious infection. Fungi were also
identified. Half of the serious infections were observed in patients receiving
daily prednisone therapy. Sixteen percent of infections were observed when
cyclophosphamide was given alone.
Bradley et al observed serious infections in a small group of patients with
systemic vasculitis treated with cyclophosphamide [103]. More than half the
patients had infections detected during 200 patient-months of follow up. The rate
of infections in SLE patients with nephritis treated with cyclophosphamide plus
low-dose steroids is the same as that seen in patients treated with high-dose
steroids alone. Pulse cyclophosphamide therapy for lupus nephritis is associated
with rates of infections similar to those of daily cytotoxic treatment [104].
Azathioprine and its metabolite inhibit protein synthesis. Treatment results in
lymphopenia and suppressed immunoglobulin synthesis [60]. Neutrophil func-
tion seems to remain intact with azathioprine therapy. Neutropenia may result
from bone marrow suppression, however. This neutropenia seems to be dose
dependent. In a large study comparing cytotoxic medications in rheumatoid
arthritis patients, the rate of infection was lower with azathioprine than with
cyclophosphamide or methotrexate. Opportunistic infections are rarely reported
934
Table 3
Predominant immunologic defects and pathogens associated with selected pharmacologic agents used in the treatment of rheumatic diseases
Abnormality Agent Bacterial Fungal Protozoal Viral
Qualitative defect of Corticosteroids Gram-positive Candidia spp
S.B. Greenberg / Crit Care Clin 18 (2002) 931–956

phagocytic function Cyclophosphamide and Staphylococcus aureus Aspergillus spp
or neutropenia other alkylating agents Streptococcal spp
Azathioprine Nocardia spp
Gram-negative
Escherichia coli
Klebsiella pneumoniae
Pseudomonas aeruginosa
Other Enterobacteriaceae
Defective cell-mediated Corticosteroids Mycobacterium spp Histoplasma capsulatum Pneumocystic carinii Cytomegalovirus
immunity Cyclophosphamide Listeria monocytogenes Coccidioides immitis Toxoplasma gondii Epstein-Barr virus
Other alkylating agents Salmonella spp Cryptococcus neoformans Strongyloides stercoralis Varicella-Zoster virus
Azathioprine Nocardia spp
Methotrexate
Cyclosporin A
Defective humoral Cyclophosphamide Streptococcus pneumoniae
immunity Corticosteroids (high-dose) Haemophilus influenzae
Azathioprine
From Segal BH, Sneller MC. Infectious complications of immunosuppressive therapy in patients, with rheumatic diseases. Rheum Dis Clin North Am 1997;23:219 – 37;
with permission.
in patients receiving azathioprine alone. When azathioprine is used in combina-

tion with steroids, opportunistic infections are recorded.
Methotrexate is immunosuppressive in high doses but is less so in the dosages
used in treating rheumatoid arthritis [105]. Low-dose methotrexate can inhibit
immunoglobulin synthesis and neutrophil chemotaxis and can cause bone
marrow suppression [106,107]. Antibiotics with antiproliferative properties (ie,
trimethoprim-sulfamethoxazole) should be used with caution in patients receiving
methotrexate therapy. The infection rate in methotrexate-treated rheumatoid or
psoriatric arthritis patients ranges from 0 to 20% per year [108 – 110]. Pneumo-
cystis carinii pneumonia and herpes zoster are the most commonly reported
opportunistic infections [111,112]. Less commonly identified opportunistic
pathogens include Nocardia, Cryptococcus, Histoplasma, Aspergilla, Mycobac-
terium tuberculosis, and Listeria [107,113– 120]. Although uncommon, low-dose
weekly methotrexate is associated with opportunistic infections as early as a few
weeks to several years after starting therapy [121,122]. When methotrexate was
given with corticosteroids in Wegener’s granulomatosis, Pneumocystis carinii
pneumonia was reported in several patients [101].
Cyclosporin A binds to cyclophilin, an endogenous intracellular protein,
resulting in a complex that inhibits the activity of calcineuin. Calcineuin is
required for transmitting activity signals from the T-cell receptor [123]. Infec-
tions with cyclosporin therapy relate to those associated with defective cell-
mediated immunity.
Lymphocytotoxic monoclonal Ab, CAMPATH-IH, is a humanized monoclonal
antibody that recognizes the antigen CD52 that is expressed on B, T, and natural
killer (NK) cells and macrophages. The beneficial effects of this therapy in rheu-
matoid arthritis patients have been transient. Although NK cells, B cells, and
monocytes returned to normal levels within 3 to 6 months, CD4+ and CD8+ T cells
remained low for years [22]. Among 13 deaths in patients previously receiving
CAMPATH-IH for RA, 4 had pneumonias as the underlying cause of death.
Among 18 patients with major infections after CAMPATH-IH therapy, septicemia
and pneumonia were the most frequent types of infections. Minor infections
following CAMPATH-IH therapy included herpes simplex, varicella-zoster virus
infections, and bronchitis. The authors conclude that there was no unusual increase
in number or types of infections in these RA patients treated with CAMPATH-IH.
New therapies for rheumatoid arthritis (infliximab and etanercept)

Two new biologic agents used in the treatment of rheumatoid arthritis target
tumor necrosis factor-a (TNF-a). A chimeric IgG1 monoclonal antibody with
high affinity for human TNF-a, infliximab has been shown to improve joint pain
and swelling in RA patients [124 – 129]. Recent reports, however, have shown
an increase in cases of tuberculosis, listeria, and histoplasmosis (Table 4)
[130 –132]. Etanercept is a recombinant human TNF receptor protein that binds
TNF-a. Because of the drug’s half-life, it can be administered subcutaneously
Table 4
Reported infections with treatment of RA with biologic response modifiers infliximab and etanercept
Infection Infliximab treatment Etanercept treatment
Mycobacterium tuberculosis 92 11
Histoplasmosis 9 1
Pneumocystis carinii 12 5
Coccidioidomycosis 2 0
Cryptococcosis 2 3
Adapted from US Food and Drug Administration. 2001. Available at: http://vapbm.org/criteria/
lef_etan_infcriteria.pdf. Accessed October 1, 2001; with permission.
two times per week. It has been reported to be associated with tuberculosis
infections [133], although a recent study has suggested that tuberculosis in RA
patients increased before these new therapies became available [134].
Clinical presentations in systemic lupus erythematosus

Fever in SLE patients is commonly observed with disease activity [135,136].
Eighty percent of patients will have fever documented at least once during this
illness. In one series, only 23% of febrile episodes were caused by infections
[137]. Clinically it was difficult to distinguish infection from active SLE. Shaking
chills occurred in significantly more patients with proven infections (68% versus
27%). Neutrophilic leukocytosis was detected more frequently in febrile patients
with infection.
In all patients with rheumatic diseases, fever should prompt an immediate
evaluation. Besides a complete history and physical examination, a chest roent-
genogram, blood and other appropriate cultures, and assessment of the under-
lying disease activity are all appropriate. Skin lesions in a febrile patient with
rheumatic disease should be examined carefully and biopsied for culture and
pathologic review.
If signs and symptoms of pneumonia are present, careful review of laboratory
and clinical findings should help distinguish infection from active rheumatic
disease or a drug reaction [138,139]. Bacteria are the most common cause of
pneumonia and reflect the agents in the community. The most frequently detected
opportunistic pathogen in rheumatic diseases is Pneumocystic carinii pneumonia,
although fungi, mycobacteria, Nocardia, and cytomegalovirus have also been
reported [17,20,67,103,140 – 142]. Onset of symptoms over a few days points to a
bacterial cause. A progressive course over days to weeks is more suggestive of an
opportunistic pathogen or active rheumatic disease flare. Exposure to individuals
with tuberculosis should be sought. History of travel to other countries or regions
of the United States should be obtained [143]. Exposure to young children with
acute respiratory viral illness should also be reviewed.
On roentgenogram studies, pulmonary infiltrates may have varying patterns
that suggest either an infectious or noninfectious diagnosis (Table 5) [144 – 148].
If the patient is producing sputum, a Gram’s stain and culture should be sent to
Table 5
Differential diagnosis of pulmonary infiltrates in patients with rheumatic diseases
Radiographic pattern Infectious causes Noninfectious causes
Localized infiltrates Bacterial pneumonia Wegener’s granulomatosis
(including Legionella spp) Churg-Strauss syndrome
Mycobacteria spp Pulmonary embolus
Opportunistic fungi
Aspergillus spp
Histoplasma capsulatum
Coccidioides immitis
Cryptococcus neoformans
(uncommon)
Diffuse infiltrates Pneumocystis carinii Systemic lupus erythematosus
Bacterial pneumonia Rheumatoid arthritis
(hematogenous spread) Microscopic polyangiitis
Mycoplasma pneumoniae Wegener’s granulomatosis
Chlamydia spp Churg-Strauss syndrome
Mycobacteria spp Scleroderma
(miliary pattern) Sjögren’s syndrome
Opportunistic fungi Dermatomyositis/polymyositis
Viral Pulmonary edema
Influenza virus Drug-induced
Cytomegalovirus Methotrexate
Varicella-Zoster virus (rare) Cyclophosphamide (rare)
Azathioprine (rare)
Nodules or nodular Septic emboli Wegener’s granulomatosis
infiltrates Staphylococcus aureus Churg-Strauss syndrome
Pseudomonas aeruginosa Rheumatoid arthritis
Mycobacteria spp Lymphoma
Nocardia spp
Opportunistic fungi
Adapted from Segal BH, Sneller MC. Infectious complications of immunosuppressive therapy in
patients with rheumatic diseases. Rheum Dis Clin North Am 1997;23:219 – 37; with permission.
the laboratory. Thoracentesis should be performed if pleural fluid is detected.

Depending on the severity of the illness and the extent of the pulmonary
infiltrates, a more expedient approach may require bronchoscopy with broncho-
alveolar lavage (BAL) and transbronchial biopsy. The isolation of Candida from
respiratory secretions does not usually indicate infection but rather colonization.
Aspergillus spp recovered from respiratory secretions may reflect either coloniza-
tion or invasive disease. Only the detection of Aspergillus or Candida from tissue
samples is the standard for diagnosing these opportunistic fungal infections [149].
Cytomegalovirus recovered from BAL should also be interpreted with caution
when quantitative cultures or tissue biopsy specimens yield evidence of invasive
viral infection [150]. Open-lung biopsy should be reserved for patients with
unresponsive localized lesions or cavities.
Central nervous system infections in patients with rheumatic diseases may be
difficult to differentiate from the clinical manifestations produced by the diseases
themselves [151,152]. Although CNS infections have been reported in Wegener’s

granulomatosis, polyarteritis nodosa and Behcet’s disease, they are most difficult
to diagnose in SLE because of the high frequency of neuropsychiatric symptoms
[153]. Wong et al reported that 50% of episodes of neuropsychiatric disease in
SLE patients were caused by a CNS or systemic infection [154]. Although other
series reported a lower incidence of CNS infections, they agree with the difficulty
in clinically distinguishing infections from CNS lupus [155,156]. These patients
may not have the typical signs and symptoms of meningitis. Therefore, patients
with unexplained headache, personality changes, confusion, and focal neurologic
findings should have immediate computed tomographic (CT) scan or MR
imaging and lumbar puncture.
Serum markers of infection in systemic lupus erythematosus

C-reactive protein (CRP) is an acute-phase protein of the innate host defense
against bacterial pathogens. Elevated CRP levels in serum of SLE patients have
been studied as a marker of disease activity versus the presence of coexistent
infection. In a recent retrospective case control study in Korean patients with
SLE, Suh et al report that CRP levels greater than 50 mg/L are suggestive of
infection [157]. Similar findings were reported in earlier studies [158 – 160].
C-reactive protein levels during SLE flares can range from 1 to 375 mg/L with a
median level of 16.5 mg/L [161]. Systemic lupus erythematosis flares associated
with serositis had higher median levels (76 mg/L) than seen in flares without
serositis (16 mg/L) [161]. Local infections had CRP levels between 10 mg/L and
50 mg/L. Fever may be observed in infected SLE patients even with nonelevated
CRP levels [162]. In a recent study, elevated interleukin (IL)-1 receptor
antagonist levels, but not IL-6, IL-1b or TNF-a levels, were markers for elevated
CRP levels in untreated SLE patients [163].
Elevated serum ferritin levels have been reported to be another marker of SLE
disease activity in untreated patients [164]. It is unclear whether ferritin levels can
be used to distinguish infection from disease activity. Fibrinogen level, another
acute phase reactant, was found to increase with age regardless of SLE disease
activity [165].
Procalcitonin (PCT) levels in the serum have been reported to increase in
bacterial or fungal infections but not in viral infections. A recent prospective
study in 19 patients with SLE and fever reported elevated PCT levels in nonviral
infection in 9 SLE patients but not in 3 viral-infected SLE patients and not in 7
patients with an SLE flare [166]. The elevated PCT levels returned to normal
during defervescence. Procalcitonin and CRP levels may prove useful when used
together in febrile SLE patients.
Mortality from infections in systemic lupus erythematosus

One of the most common causes of death in SLE patients is infection
[46,167,168]. Three recent cohort studies have documented the importance of
infections as a cause of death in these patients, and many other studies over
3 decades from many different countries have reported infectious death rates of
0 to 67%, with a mean of 24% [4,30,148]. Six studies following patients from the
onset of diagnosis (cohort studies) have reported infectious death rates from
6% to 67%, with a mean rate of 24.5% [4,24,30,32,40,41,43,46,48,167,169,170].
Infectious causes of death may be underreported, because autopsy studies have
found several opportunistic infections that had not been diagnosed before
death [36,67].
Serious infections in systemic lupus erythematosus

Serious infections in SLE patients often involve theCNS, blood, lungs, or
urinary tract [171 – 174]. The commonly isolated organisms that cause meningitis
in non– SLE patients also infect SLE patients. Other opportunistic organisms,
such as Legionella, Nocardia, Cryptococcus, Mycobacteria, Toxoplasmosis, and
Listeria, are also important causes in corticosteroid-treated SLE patients [175 –
180]. The presentation and etiology of bacteremia or fungemia in SLE patients is
similar to that in other patients [181]. Disseminated neisserial and nontyphoid
Salmonella infections, however, seem to be more common in SLE patients [182 –
184]. Community-acquired pneumonia occurs with the same pathogens in SLE
patients as in the general population. Systemic lupus erythematosis patients
treated with corticosteroids or immunosuppressive medications may have pneu-
monia caused by Legionella, Pneumocystis carinii, Nocardia, Mycobacterium
tuberculosis, or Cryptococcus neoformans [185 – 190]. Urinary tract infections
caused by gram-negative bacteria are common in SLE patients and may be
accompanied by septicemia [5]. Candida albicans is a common cause of urinary
tract infections in corticosteroid-treated SLE patients. Skin infections such as
cellulitis are caused by Staphylococcus aureus and group A streptococci. Herpes
zoster frequently affects steroid-treated SLE patients. Cases of secondary syphilis
have been reported to mimic SLE [191].
Risk factors for serious bacterial infections include cytotoxic medications,
corticosteroids, proteinuria, renal insufficiency, and active SLE [192,193]. Up to
37% of patients treated with cyclophosphamide develop a serious infection [192].
To most clinicians, the ability to differentiate an SLE flare from infection is a
significant challenge. Because there is overlap between the organ involvement by
SLE with that seen with infectious organisms, early recognition and appropriate
treatment may be difficult [194,195].
Lupus cerebritis has many of the clinical findings seen in bacterial meningitis
[196,197]. A stiff neck is far less common in lupus cerebritis than in bacterial
meningitis [153]. Findings in the cerebrospinal fluid with bacterial meningitis
include neutrophilic pleocytosis, low cerebrospinal fluid (CSF) glucose, and
increased lactic acid levels. Findings are similar in lupus cerebritis, except the
lactic acid levels are normal. A decreased C4 level in the CSF is helpful in the
diagnosis of SLE cerebritis [153]. Although earlier publications have suggested
that there are typical changes on CT and MR imaging scans of the brain in lupus
cerebritis, more recent series have suggested the observed abnormalities were
nonspecific [198].
Bacteria are the cause of most infections in SLE patients [36,67,169,170,
199,200]. Escherichia coli is a common pathogen, but Staphylococcus aureus and
Streptococcus pneumoniae have also been isolated [201]. Streptococcus pneumo-
niae may cause epiglottitis, pneumonia, sepsis, or soft tissue infections [202 – 204].
Nocardia infections of the lung and CNS have been reported but are infrequent.
Salmonella infections
Salmonella are aerobic gram-negative bacilli that can cause serious infections
in SLE patients [182,205 – 208]. Salmonella are grouped by the carbohydrate side
chain on the cell wall. Salmonella typhosa belong to group D Salmonella.
Nontyphoid salmonella bacteremias, especially group B and D, have been
reported in SLE patients [184,209]. Most cases occur during periods of active
SLE and may be the presenting illness of SLE. Most of these patients have been
treated with corticosteroids or other immunosuppressive drugs. Systemic lupus
erythematosus patients may be prone to Salmonella infections because of
inadequate opsonization, impaired mononuclear phagocytosis, hyposplenism, or
low serum complement levels. Although fever at presentation is the rule, 15% to
20% of patients may be afebrile. Clinical syndromes include gastroenteritis,
arthritis, and pneumonia [210,211]. Other less common diagnoses included
cellulitis, osteomyelitis, urinary tract infection, or meningitis [212 –214]. Most
patients are not toxic or septic on admission. Laboratory findings include anemia,
lymphopenia, and hypoalbuminerima. Elevated CRP levels ( > 10 mg/L) are
commonly reported. Anti-dsDNA is raised in more than 85% of patients.
Recurrences following treatment have been seen.
With Salmonella bacteremia, a 2-week course of appropriate antibiotic is
indicated [215]. Salmonella gastroenteritis without bacteremia should not be
treated with antibiotics, because antibiotics have been shown to cause prolonged
fecal carriage and increased relapse [216]. Death is uncommon but can occur. If
recurrence or persistent bacteremia is observed, a careful search for carriage in
the gallbladder or detection of a mycotic aneurysm, arthritis, or osteomyelitis
should be undertaken.
Neisseria infections
Neisserial infections have been reported in SLE and may present clinically as
a lupus flare [183]. These patients are often young women with renal disease
and low C3 and C4 levels. Complement deficiencies may be acquired or
congenital. Arthritis is a common presentation of disseminated neisserial
infection [217]. Meningitis and, less commonly, endocarditis have been reported
[218 –220]. Although there are few data on the usefulness of immune response
to meningococcal vaccine in SLE patients, many authorities recommend
vaccination of these SLE patients [221].
Mycobacterial infections
Mycobacteria tuberculosis has been found in SLE patients, especially in
geographic areas with a high rate of purified protein derivative (PPD) positivity
[42,222 – 225]. Extrapulmonary disease is common [226 –228]. Most of the
patients were receiving corticosteroid or immunosuppressive therapy [229,230].
A negative PPD in patients receiving corticosteroids cannot be used to rule out
tuberculosis. Cases of nontuberculosis mycobacterial infections in SLE patients
have been reported [231 – 235].
Fungal infections
The fungi reported to cause infection in SLE patients are Candida, As-
pergillus, Cryptococcus, and Pneumocystis carinii [236 –239]. Other fungi
have been rarely reported [76,240 –247]. In the series by Hellman et al, Can-
dida spp was the opportunistic infection leading to death in 6 of 24 patients
[67]. Systemic lupus erythematosis patients receiving immunosuppressive
drugs or antibiotics in the hospital should be considered candidates for these
fungal infections.
Pneumocystis carinii pneumonia (PCP) is an uncommon but potentially fatal
infection in SLE patients [248 – 254] and in other patients with connective tissue
diseases [255 –257]. One study reported on the frequency of PCP in Wegener’s
granulomatosis patients who were lymphopenic and immunosuppressed [258].
Lymphopenia was also found in SLE patients who developed PCP [250]. A
diagnosis of interstitial pulmonary fibrosis was made by characteristic chest
rroentgenogram or CT scan findings and was reported in all the SLE patients who
developed PCP, but it is unclear from the report when interstitial pulmonary
fibrosis was found in relation to clinical PCP. Of seven patients with PCP in this
series, three died.
Viral infections
Most viral infections in SLE patients have not been proved to be more
frequent or more severe than in non –SLE patients [259,260]. Herpes zoster has
been reported to occur more frequently, but not with more disseminated disease,
than in other immunosuppressed patients [67,261 – 263]. Cytomegalovirus viruria
was not shown to be associated with serologic activity in SLE patients followed
longitudinally [264,265] but may be associated with SLE flares [266]. Other
herpesviruses have not been found to cause SLE complications or to lead to
increased disease activity [5,267 –271]. Human immunodeficiency virus infec-
tion has been reported to be associated with improvement in SLE patients and
with the loss of autoantibodies [272]. Progressive multifocal leukoencephalopa-
thy has also been reported in SLE patients [273].
Human parvovirus B19 infection is associated with fever, anemia, thrombo-
cytopenia, and leukopenia [274]. Antinuclear antibodies may also be detected
following this infection [275]. Therefore, active SLE or juvenile rheumatoid
arthritis must be in the differential diagnosis when considering active parvovirus

B19 infection [276,277]. In addition, occasional SLE patients with human
parvovirus B19 infection have had flares reported during the acute infection
[278 –280].
Infections in rheumatoid arthritis

Early studies with RA patients suggested that infections account for approx-
imately 25% of all deaths [29,59,85,105]. As with SLE, it has been difficult to
separate the effects of immunosuppressive drugs used in treatment from the
disease itself. Low-dose methotrexate treatment in RA patients seems to increase
infection rates [5,108]. Postoperative infections in RA patients have also been
related to methotrexate use [121]. Stuck et al found no increased risk of infection
among patients taking prednisone at a daily dose of less than 10 mg or a
cumulative dose of less than 700 mg [61].
Two retrospective case-control studies of infections in RA patients found no
increased rate in common infections compared with patients with osteoarthritis
[281,282]. These studies were of short duration and were based on self-reported
hospitalized patients [11].
A recent population-based study was reported in abstract form from an
incidence cohort in Rochester, Minnesota, between 1955 and 1994 [81].
Rheumatoid arthritis patients were followed from first diagnosis along with an
age- and sex-matched control group for a mean of 12.7 and 15 years, respectively
(Table 6). The total case incidence per 100 person-years for all infections was
19.23 versus 12.65 for RA patients and the control group, respectively (rate
ratio = 1.52). Septic arthritis and osteomyelitis had rate ratios of 14.87 and 10.62,
respectively. The rates of skin and soft tissue infections were approximately three
times higher in RA patients than in controls. Septicemia, pneumonia, lower
Table 6
Incidence cohort of RA patients followed from 1955 – 1994 at the Mayo Clinic
Infection Rate ratio
Septicemia 1.5
Septic arthritis 14.9
Osteomyelitis 10.6
Pneumonia 1.6
Lower respiratory tract infection 1.9
Urinary tract infection 1.1
Skin or soft tissue 3.3
Intra-abdominal 2.8
Other 2.0
609 rheumatoid arthritis cases followed 12.7 years (mean); 609 controls followed 15 years (mean).
Data from Doran MF, Pond GR, Crowson CS, et al. Risk of infection in persons with rheumatoid
arthritis compared to controls: a population-based study [abstract]. Arthritis Rheum 2001;44:S105.
respiratory tract, and intra-abdominal infections were also more frequent in RA

patients than in the control group.
Septic arthritis is a major infection in RA patients [80,283 –287]. Nolla et al
reported on recent cases of septic arthritis in RA patients seen between 1990 and
1998 [286]. All patients had long-standing disease and were being treated with
corticosteroids. Isolated bacteria included Staphylococcus aureus, gram-negative
bacilli, anaerobes, and Streptococcus pneumoniae. The principal source of
infection is thought to be the skin. There was often a delay in diagnosis of a
few days to several weeks. Half of the patients had fever. Two patients died. Of
those who lived, most had worsening of their joint function.
Older series have commented on the importance of Staphylococcus aureus
in septic arthritis [288 – 290]. Less common organisms have been recovered
in individual cases [291 – 298]. Recent studies have pointed to the emergence
of Streptococcus pneumoniae as a cause of septic arthritis in these patients
[299 –301].
Most cases of septic arthritis are monoarticular, but 10% to 20% may be
polyarticular [80,288]. The joints most frequently infected are the knee, elbow,
and wrist. Patients with poor outcomes often have delayed diagnosis [302]. All
acutely inflamed joints in RA patients should be aspirated for cell count, Gram’s
stain, and culture of the synovial fluid. Repeated needle aspiration or surgical
drainage should be considered in addition to prompt antibiotic therapy.
Respiratory infections, especially pneumonia, have been reported with RA
[303,304]. In addition to the usual community-acquired agents, opportunistic
pathogens such as atypical mycobacteria and Pneumocystis carinii can be found
[305 – 309]. As in SLE, these opportunistic pathogens may be related to
immunosuppressive therapy and not to RA per se [96]. Recent experience with
infliximab and etanercept has highlighted the risk of tuberculosis and fungal
infections in RA patients treated with these agents [126,127].
Vaccination for systemic lupus erythematosus and rheumatoid

arthritis patients
Because of the morbidity associated with pneumococcal and influenza virus
infection, it has been recommended that SLE and RA patients receive approved
inactivated vaccines [310,311]. The two major issues in vaccine administration of
these patients are (1) the expected immune response following vaccination, and
(2) the potential for worsening the underlying disease. Recent studies have failed
to find a relationship between the administration of the pneumococcal vaccine
and the influenza virus vaccine and SLE or RA flares or decrease in clinical
function by these patients. Some studies, however, have suggested that these
patients may hae a less-than-optimal immune response to these vaccines.
Meningococcal vaccines should probably be given to SLE patients. The long-
term safety of hepatitis B vaccine or live attenuated viral vaccines has not been
studied systematically in controlled trials.
Summary
Immunocompromised patients with rheumatic diseases have an increased risk
of infections. A major risk factor for infection seems to be the immunosuppres-
sive therapy used. Newer therapies for RA may lead to increased rates of
infection by opportunistic pathogens such as Mycobacteria tuberculosis. Because
disease manifestation may mimic signs and symptoms of infection, prompt
diagnosis may be difficult. Familiarity with the likely infections and their causes
should aid in obtaining the appropriate culture specimens.
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Crit Care Clin 18 (2002) 931 – 956

Infections in the immunocompromised

Infections in immunocompromised patients with rheumatic diseases cause

* Department of Medicine, Baylor College of Medicine.

Predisposing factors to infection

Immunologic effects of corticosteroid use

Infections in corticosteroid-treated patients are those associated with defective

Other immunosuppressive therapies

S.B. Greenberg / Crit Care Clin 18 (2002) 931–956

in patients receiving azathioprine alone. When azathioprine is used in combina-

New therapies for rheumatoid arthritis (infliximab and etanercept)

Clinical presentations in systemic lupus erythematosus

the laboratory. Thoracentesis should be performed if pleural fluid is detected.

themselves [151,152]. Although CNS infections have been reported in Wegener’s

Serum markers of infection in systemic lupus erythematosus

Mortality from infections in systemic lupus erythematosus

Serious infections in systemic lupus erythematosus

arthritis must be in the differential diagnosis when considering active parvovirus

Infections in rheumatoid arthritis

respiratory tract, and intra-abdominal infections were also more frequent in RA

Vaccination for systemic lupus erythematosus and rheumatoid

[214] Sanchez-Guerrero J, Alarcon-Segovia D. Salmonella pericarditis with tamponade in systemic

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