Graciela S Alarcon MD MPH

Division of Clinical Immunology and Rheumatology, Department of Medicine, The University of Alabama at Birmingham, Faculty Office Tower, 510 20th Street South, Birmingham, AL 35294-3408, USA

Systemic lupus erythematosus (SLE), scleroderma, and polymyositis/der-matomyositis (PM/DM) are autoimmune diseases with high morbidity and mortality [1]. The important role infections play in these diseases has been documented in the literature over the years [2-17]. This article reviews the role of infections in these three disorders, emphasizing in each (1) the predisposing factors for the development of infections, (2) the effect of infections on mortality, and (3) the most common microorganisms involved in these infectious processes.

Infections in systemic lupus erythematosus

Infections are responsible for 30% to 50% of the morbidity and mortality in children and adults who have SLE [2,3,5,11-13,17-24]. These infectious processes usually result from common microorganisms [2,11,14,16,17,20,25-28], but opportunistic infections also may occur and are important causes of death in patients who receive corticosteroid and immunosuppressive therapy [9,18-20,25,29-32].

Portions of this article originally appeared in Juarez M, Misischia R, Alarcon GS. Infections in systemic connective tissue diseases: systemic lupus erythematosus, scleroderma, and poly-myositis/dermatomyositis. Rheumatic Disease Clinics of North America 2003;29(1):163-84.

Supported by MCRC grant M01-RR00032 from the National Institute of Arthritis and Musculoskeletal and Skin Disorders.

E-mail address: [email protected]

0891-5520/06/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.idc.2006.09.007 id.theclinics.com

Predisposing factors

Genetic predisposition to immune dysfunction

Patients who have SLE with inherited complement deficiencies may present abnormalities of all complement proteins, particularly those of the early classic pathway [33]. Patients who have SLE with early complement deficiencies have a higher risk for infections caused mainly by Streptococcus pneumoniae, whereas patients who have SLE with late complement deficiencies show a greater susceptibility to infections by Neisseria meningitidis and N gonorrhoeae [33,34].

Variant alleles in the coding portion of the mannose binding lectin (MBL) gene have been associated with lower levels of MBL, a protein that plays an important role in the phagocytosis of microorganisms and has a function similar to C1q [35]. Patients who have SLE homozygous for MBL variant alleles also have a significantly higher risk for developing infections, such as pneumonia by S pneumoniae. It has been demonstrated, for example, that the annual incidence of infections requiring hospitalization is four times higher in these patients who have SLE than in those heterozygous for the variant allele or homozygous for the normal allele [35,36].

Abnormalities in the immune system

Patients who have SLE have lower levels of complement proteins and a reduced number of cellular complement receptors (CR1, CR2, CR3) [37,38]; this is particularly the case for B cells and polymorphonuclear leukocytes (PMNs) [39]. These abnormalities may increase the risk for infections [34]. Petri and colleagues [13] described lower C3 levels 1 year later among patients who had lupus who required hospitalization for infection, and Kim and coworkers [40] reported reduced complement levels among those patients who died of infection.

SLE can affect various cell functions, and PMNs show many abnormalities. Chemotaxis, recognition of microorganisms, phagocytosis, and oxida-tive metabolism usually are altered [37,38]. In active SLE, a decreased production of interleukin 8 (IL-8) by PMNs resulting in an altered acute inflammatory response has been described [41]; finally, elevated levels of gran-ulocyte macrophage-colony stimulating factor have also been described in SLE [24]. These PMN abnormalities predispose patients who have SLE to the development of infections [37,38,41].

Several macrophage and monocyte functions, including phagocytosis and oxidative metabolism, also are impaired in patients who have SLE, thus increasing the risk for infections [38]. These abnormalities result from the presence of autoantibodies directed against all three types of Fc gamma receptors (FcgR) [38,42] and from a decrease in the production of tumor necrosis factor alpha (TNFa) [38,42].

During exacerbations of SLE, patients present with decreased levels of T cells and diminished activity of T-helper cells against viral antigens, toxoids, and alloantigens [38,43]. Prolonged corticosteroid therapy also impairs T-cell immunity producing redistribution of T cells, lymphopenia, and inhibition of T-cell activation and proliferation [44]. These T-cell abnormalities result in a higher risk for infections particularly by intracellular microorganisms [19,43-47]. The spleen, through its system of macrophages, is involved in the clearance of microorganisms, thus preventing them from dissemination [45]. When splenic function is impaired, as it is in some SLE patients, the risk for developing severe infections caused by encapsulated microorganisms, such as S pneumoniae, N meningitidis, and N gonorrhoeae increases [34,45,48].

Disease activity

Disease activity (quantified by validated activity scores) has been found to be an independent risk factor for the occurrence of infections [12,13,17,49-51]. Immune abnormalities, such as decreased complement levels and dysfunction of PMNs, macrophages, monocytes, and T cells, seem to be more pronounced during periods of SLE activity [37,38,41,43]. Duffy and colleagues [49] found that disease activity (quantified by the SLE disease activity index [SLEDAI]) is associated with infections independent of the duration of SLE and the dose of prednisone used. Petri and co-workers [13] demonstrated that SLE activity (quantified by the lupus activity index and the SLEDAI) is a predictive factor for hospitalization because of infections, even after carrying out statistical adjustment for corticosteroid use [13]. Chen and colleagues also have shown that disease activity is a risk factor for the occurrence of infections in hospitalized children who have SLE [23]. Finally, Wu and coworkers have shown that disease activity as measured by the SLEDAI is a risk factor for the occurrence of salmonella osteomyelitis in patients who have SLE [52]. There are, however, studies that dispute this association [26,53] and others in which disease activity has not been found to be a risk factor for the occurrence of infections after carrying out adequate multivariable analyses [5,11,29,54].

Corticosteroids and other immunosuppressive drugs

The use of corticosteroids has been associated with increased occurrence of infections in patients who have SLE [5,11,13,19,29,49-51,55]; it is not clear, however, whether this risk relates to doses larger than 10 mg per day [13], incremental doses of corticosteroids [29], or the use of the intravenous route [12,13]. Probable reasons underlying this risk include decreased production of cytokines by suppression of nuclear factor kappa B (NFkB) [56] and the inhibition of different PMN, monocyte, and T-lymphocyte functions [44].

Cyclophosphamide is now commonly used for the treatment of diffuse proliferative glomerulonephritis and other serious manifestations of SLE otherwise unresponsive to high doses of corticosteroids [57]. Unfortunately, the use of cyclophosphamide increases the risk for severe infections in patients who have SLE [11,31,58]. Risk factors strongly associated with infections in SLE patients who receive cyclophosphamide are the sequential use of intravenous and oral cyclophosphamide and a leukocyte count less than 3000 cells/mL3 [58]. These patients have an increased risk for developing fatal opportunistic infections [19,58]. This risk is greater when patients also are receiving high doses of corticosteroids [21,58].

Although less long-term data and overall experience are available with mycophenolate mofetil, the data from some but not all of the randomized clinical trials support the fact than infections are much less common with this agent than with cyclophosphamide or even azathioprine [59-61].

Procedures

Certain procedures have been associated with increased risk for infections in patients who have SLE. Patients who receive both plasmapheresis and pulses of cyclophosphamide are at greater risk for developing severe and fatal bacterial and viral infections than patients who have comparable clinical features receiving cyclophosphamide alone [62]. The risk is increased because the levels of B cells, T cells, and immunoglobulins, and consequently their functions, are markedly decreased as a result of plasmapheresis, particularly when this therapy is combined with immunosuppressive therapy [62]. Patients who have SLE receiving chronic peritoneal dialysis have a greater risk for peritonitis or catheter-related infections than patients who do not have SLE (or diabetes) who have comparable clinical characteristics [63]. Im-munoablation, with or without autologous stem cell transplantation, has emerged as an alternative treatment of patients who have SLE not responding to other treatment modalities [64]. Data are scarce, and follow-up is still short, but some severe infections, such as herpes zoster (HZ), herpes simplex, and Pneumocystis carinii pneumonia (PCP) have been reported in these patients, most likely resulting from profound immunosuppression [64].

Infections as a cause of death

Infection is the primary cause of death in patients who have SLE in developing countries [20,65-72]. In a Chinese cohort of patients who had SLE followed from 1992 to 1996, 66% of deaths were caused by infections [70]. In a series of autopsies performed in SLE patients from Brazil, infections were responsible for 58% of all deaths; 34% of deaths were attributed to active SLE [20]. In developed countries, infection also is one of the most important causes of death among SLE patients and is considered the first or second most common cause of mortality in several studies [2,3,11,16,18,19,40,73,74]. In the multicenter European study of 1000 patients followed for more than 5 years, infections and disease activity were found to be responsible for more than half of all deaths [3]. Similar data come from a study performed in France between 1960 and 1997; in this study active SLE and infections were responsible for 28% and 20% of deaths, respectively [11]. This high rate of mortality from infections is probably the result of the more aggressive use of corticosteroids, immunosuppressive drugs, and support therapy (including dialysis and critical care) in controlling the activity and complications of SLE.

Opportunistic infections are emerging as important causes of death in patients who have SLE in both developed and developing countries. These infections frequently are associated with the increased use of high doses of corticosteroids and immunosuppressants and often are diagnosed only post mortem [9,18-23,58]. Table 1 summarizes the published data regarding infections as a cause of death in SLE; however, the different studies summarized in this table are not directly comparable because their methodologies vary significantly.

Types of infections occurring in systemic lupus erythematosus

Infections cause 25% to 50% of morbidity in patients who have SLE, and major infections are important causes of hospitalization. These infections have been described in different studies that are summarized in Table 2. The most frequent infection sites and most common microorganisms affecting SLE patients are presented in Table 3. Like the studies summarized in Table 1, the studies presented in these tables are not directly comparable because their methodologies vary substantially.

Bacterial infections

Common bacteria are responsible for most infections in patients who have SLE [3,5,9-11,13,16,17,20,50,53,58]. The most frequently described bacteria are Gram-negative bacilli [5,9,17,18,40] and Gram-positive cocci [5,10,16]. Among the Gram-positive bacteria, Staphylococcus aureus is a common pathogen that often gains entry through injured skin [10,11]. Infections with S aureus may be localized to the integument [10], bones, and joints [55]; however, severe and fatal infections, such as bacteremia [16,18,19,23,58], pneumonia [14], and catheter-related infections [11], also may occur.

S pneumoniae in patients who have SLE typically causes pneumonia [11,16,17]; however, meningitis [16], sepsis, [16,66,75], and cutaneous infections also have been described [76]. The more severe presentations occur in those patients who either have associated inherited deficiencies of the early complement pathway or splenic dysfunction [33,34,38,45,48].

Infections with Listeria monocytogenes are rare, but meningitis and sepsis have been reported in patients receiving high doses of corticosteroids or immunosuppressive therapy [58,77] and in those who have active SLE [77]. Listeriosis therefore should be ruled out in critically ill patients who have SLE who present with infections of the central nervous system (CNS) [77].

Table 1

Mortality from infections in patients who have systemic lupus erythematosus

Author/year

Deaths Deaths

(all causes) (infection) Causal microorganism (%)

Study characteristicsa

Place

Total patients

Ethnicity

Common/

5-Year survival

Hellmann/1987 [19]

de Luis/1990 [18]

Massardo/1991 [9]

Huicochea/1996 [68]

Chart review (1969-1985b) (deceased patients) Chart review

(1979-1987) Chart review

(1978-1990) Cohort

(1969-1983) Follow-up: ~ 11 years Chart review

(1970-1993) Chart review (1993-1997)

United States 44

Spain

Chile

(33 autopsies)

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