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].

0749-0704/02/$ – see front matter D 2002, Elsevier Science (USA). All rights reserved.

PII: S0749 -0704 (02 )00022 -2

* Department of Medicine, Baylor College of Medicine.

E-mail address: stepheng@bcm.tmc.edu (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) 931–956932

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

Table 2

Predisposing factors to infection in patients with RA

Chronic inflammation producing deformed bones and joints

Chronic use of steroid and/or immunosuppressants

S.B. Greenberg / Crit Care Clin 18 (2002) 931–956 933

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

phagocytic function

or neutropenia

Corticosteroids

Cyclophosphamide and

other alkylating agents

Azathioprine

Gram-positive

Staphylococcus aureus

Streptococcal spp

Nocardia spp

Gram-negative

Escherichia coli

Klebsiella pneumoniae

Pseudomonas aeruginosa

Other Enterobacteriaceae

Candidia spp

Aspergillus spp

Defective cell-mediated

immunity

Corticosteroids

Cyclophosphamide

Other alkylating agents

Azathioprine

Methotrexate

Cyclosporin A

Mycobacterium spp

Listeria monocytogenes

Salmonella spp

Nocardia spp

Histoplasma capsulatum

Coccidioides immitis

Cryptococcus neoformans

Pneumocystic carinii

Toxoplasma gondii

Strongyloides stercoralis

Cytomegalovirus

Epstein-Barr virus

Varicella-Zoster virus

Defective humoral

immunity

Cyclophosphamide

Corticosteroids (high-dose)

Azathioprine

Streptococcus pneumoniae

Haemophilus influenzae

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.

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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+ Tcells

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

S.B. Greenberg / Crit Care Clin 18 (2002) 931–956 935

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 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.

S.B. Greenberg / Crit Care Clin 18 (2002) 931–956936

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

Table 5

Differential diagnosis of pulmonary infiltrates in patients with rheumatic diseases

Radiographic pattern Infectious causes Noninfectious causes

Localized infiltrates Bacterial pneumonia

(including Legionella spp)

Wegener’s granulomatosis

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

(hematogenous spread)

Rheumatoid arthritis

Microscopic polyangiitis

Mycoplasma pneumoniae Wegener’s granulomatosis

Chlamydia spp Churg-Strauss syndrome

Mycobacteria spp Scleroderma

(miliary pattern) Sjogren’s syndrome

Opportunistic fungi Dermatomyositis/polymyositis

Viral Pulmonary edema

Influenza virus Drug-induced

Cytomegalovirus

Varicella-Zoster virus (rare)

Methotrexate

Cyclophosphamide (rare)

Azathioprine (rare)

Nodules or nodular

infiltrates

Septic emboli

Staphylococcus aureus

Pseudomonas aeruginosa

Mycobacteria spp

Nocardia spp

Opportunistic fungi

Wegener’s granulomatosis

Churg-Strauss syndrome

Rheumatoid arthritis

Lymphoma

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.

S.B. Greenberg / Crit Care Clin 18 (2002) 931–956 937

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

S.B. Greenberg / Crit Care Clin 18 (2002) 931–956938

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

S.B. Greenberg / Crit Care Clin 18 (2002) 931–956 939

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-

niaemay 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].

S.B. Greenberg / Crit Care Clin 18 (2002) 931–956940

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

S.B. Greenberg / Crit Care Clin 18 (2002) 931–956 941

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.

S.B. Greenberg / Crit Care Clin 18 (2002) 931–956942

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.

S.B. Greenberg / Crit Care Clin 18 (2002) 931–956 943

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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