INFECTIONS IN SYSTEMIC LUPUS ERYTHEMATOSUS AND RHEUMATOID ARTHRITIS
Section snippets
INFECTIONS IN SYSTEMIC LUPUS ERYTHEMATOSUS
Patients with systemic lupus erythematosus (SLE) have a higher infection rate than the general population. It is estimated that at least 50% of them will suffer a severe infectious episode during the course of the disease. Its prevention and treatment is particularly relevant now that improvements in the control of the disease activity and of some complications, such as renal failure, have increased significantly the life expectancy of these patients.208
Infections may be related to the
PREDISPOSING FACTORS
Predisposing factors for infection in patients with SLE are diverse (Table 1). Defects in phagocytic cell function are particularly common in periods of disease activity and in untreated patients.6, 30, 111, 140, 146, 196, 282, 283, 286 Patients with SLE have cellular immunity impairments with lymphopenia, CD4 lymphocytopenia, decrease in the production of some cytokines,23, 258 and reduction in the production of immunoglobulins and in the complement levels.60, 138, 162, 179
The elimination of
SYNDROMIC APPROACH
Patients with SLE may have local or systemic infections. The former are usually related to the decrease in the local defense mechanisms caused by the disease, renal failure, or invasive diagnostic or therapeutic procedures. Disseminated infections reflect the immunologic deficiency caused by therapy, particularly by corticosteroids.
Considering the characteristics of these patients, most common infections involve the skin, the lower respiratory tract, the urinary tract, the central nervous
VIRAL INFECTIONS IN SYSTEMIC LUPUS ERYTHEMATOSUS
For most viral infections it can be said that there is no unquestionable evidence of a higher infection rate in patients with SLE. Furthermore, it cannot be said that these infections behave more aggressively, or show more resistance to therapy or more propensity toward chronicity. Most publications include very few cases. The potential role of some viruses as inducers of SLE flares never has been proven in our opinion. The authors will discuss some viruses that deserve special attention.
VARICELLA-ZOSTER VIRUS
The varicella-zoster virus (VZV) shows a higher infection rate in patients with SLE, but disseminated or very aggressive episodes are exceptional.118 In Kahl's work, disseminated infections accounted for 11% of episodes, but this experience is not confirmed by other authors.135 Moga et al181 followed 145 SLE patients for a mean period of 7.6 years. They detected 20 VZV infections in 19 patients (13.1%) with no disseminated episode among them. Incidence was higher among patients treated with
CYTOMEGALOVIRUS
Undoubtedly, cytomegalovirus (CMV) may be a cause of severe infection in patients with SLE, but it occurred only twice in the series of fatal infections in SLE published by Hellmann et al.118
Some authors describe the ability of CMV to induce the increased expression of some autoantigens that are classically present in patients with SLE,116, 219, 241, 284, 285 but there is not enough evidence to sustain this relationship.
A longitudinal study failed to detect any relationship between CMV viruria
EPSTEIN-BARR VIRUS
Except for anecdotal cases, no clear evidence has established a relationship between Epstein-Barr virus (EBV) infection and SLE.24, 177, 257 Some SLE patients have high antibody titers against different EBV antigens,145, 170, 235, 253, 269, 281 and patients with SLE produce antibodies against Epstein-Barr nuclear antigen (EBNA) peptide and against SmD.92, 115 These suggest that molecular mimicry may play a role in the induction of anti-SmD autoantibodies.230
It never has been demonstrated that
PARVOVIRUS B19
Human parvovirus B19 may produce clinical syndromes characterized by fever, thrombocytopenia, leukopenia, and anemia together with the production of antinuclear antibodies. Consequently, it may be difficult to distinguish from SLE or juvenile rheumatoid arthritis (RA) and always must be excluded in patients who present with articular symptomatology and fever.101, 136, 171 In a series of 7 children from 6 to 15 years of age infected by human parvovirus B19, 6 presented with butterfly wings rash
OTHER VIRUSES
The association of SLE and human immunodeficiency virus (HIV) is rare and is mostly serendipitous. However, it has been reported that this coinfection resulted in the improvement of the clinical manifestations of SLE and the elimination of the autoantibodies.13, 54, 86 It is important to remember that HIV enzyme-linked immunosorbent assay (ELISA) may show false positives in patients with SLE.17
There is no solid association between SLE and other retroviruses, and no evidence suggests a higher
BACTERIAL INFECTIONS
Bacterial pathogens cause more than 90% of the infectious episodes in SLE patients in some series.118, 143, 197, 208, 209, 225 Common bacteria, such as Staphylococcus aureus, Enterobacteriaceae, and nonfermentative gram-negatives, predominate. In a series of 544 patients with SLE, gram-negative sepsis was among the most common causes of severe infection in this population.143 The authors will review some microorganisms with a high incidence or a peculiar behavior in this group of patients.
OTHER BACTERIAL INFECTIONS
Infections caused by Yersinia spp., Neisseria meningitidis, Campylobacter spp., Pasteurella multocida, Rhodococcus spp., Pseudomonas spp. or Tropheryma whippelii, among others, have been reported in the literature regarding SLE patients. Sometimes, the single peculiarity of the cases is the severity of the infection or the tendency toward recurrence in some cases.14, 33, 39, 75, 82, 133, 158, 173
There is no clear evidence of a special susceptibility of SLE patients to suffer infections caused
TUBERCULOSIS AND OTHER MYCOBACTERIAL INFECTIONS
Tuberculosis should be considered and excluded in all SLE patients, especially in those treated with corticosteroids, living in endemic areas, or with a suggestive history or positive tuberculin skin test (PPD).242
In a series of 311 SLE patients followed up from 1963 to 1979, there were 16 cases of tuberculosis, accounting for the very high incidence of 5000 per 100,000 population. A high proportion of the patients had severe extrapulmonary or miliary disease. Once again, the initial symptoms
SYSTEMIC MYCOSIS AND THE PATIENT WITH SLE
Pneumocystis carinii caused 3 of 24 lethal infections in the classical SLE series by Hellman et al.118 The clinical picture is distinctively different from HIV patients. It has a rapidly progressive course with a short prodromal period.
Although P. carinii pneumonia may take place in untreated SLE patients, this should be considered the exception that confirms the rule.95, 214 In a series of six SLE patients with P. carinii pneumonia, all were on high doses of corticosteroids and developed the
PARASITIC INFECTIONS
Systemic parasitic infections are rarely described in patients with SLE and mostly consist of case reports. In the literature of the last 20 years, we draw attention to some cases of paragonimiasis,150 toxoplasmosis in different locations,20, 66, 67 disseminated strongyloidiasis,237, 272 visceral leishmaniasis,79 and Acanthamoeba meningitis.107 It is important to differentiate the symptoms caused by these complications from those of a period of disease activity.
FEVER OF UNKNOWN ORIGIN IN SLE
One of the most crucial problems of febrile SLE patients is to distinguish if fever is caused by the activity of the disease or by an infection. First of all, it must be said that both situations may coexist. The detection of an evident focal lesion, a high count of white blood cells (WBC), the presence of chills, or the isolation of a pathogenic microorganism from a significant sample tend to indicate infection. However, no laboratory test is so definite as to be useful in a concrete clinical
VACCINATION AND PROPHYLAXIS IN SLE PATIENTS
The first point of interest regarding the use of vaccines in patients with SLE is its safety. Some reports of lupic flares after vaccination or of increased autoantibody levels raise the issue. However, studies with the pneumococcal and influenza vaccine did not prove any increase in the incidence of adverse effects or reactivation episodes.88, 147, 220, 279 With other vaccines, particularly those that use live virus, safety limits remain to be determined. The safety of hepatitis B vaccine is
INFECTIONS IN RHEUMATOID ARTHRITIS
Rheumatoid arthritis (RA) is a chronic autoimmune disease, with unknown etiology, that affects more than 4 million people in the world. The chronic inflammation may produce the destruction of the bones and joints and permanent deformities. Attempts to implicate an infective agent in the pathogenesis of RA (Parvovirus B19, Epstein-Barr virus, Mycobacterium tuberculosis) have only provided circumstantial evidence.91, 124
It has not been established whether RA implies an increase in the rate of
IMMUNOSUPPRESSION-RELATED INFECTIONS
The immunosuppression of the patient with RA is mainly pharmacologic.12, 21, 49, 76, 228 The prolonged use of antiinflammatory drugs may lead to parallel masking of the signs and symptoms of the infection. Most commonly used drugs are corticosteroids, nonsteroidal antiinflammatory drugs, methotrexate, hydroxychloroquine, leflunomide, cyclosporine, and the new α-TNF inhibitors (infliximab and etanercept).
The adverse effects of the use of corticosteroids, cyclosporine, and cyclophosphamide are
VIRAL INFECTIONS IN RA
Patients with RA may suffer all kinds of viral infections, although there is no evidence to support that the disease or the activity periods are caused by any virus.9, 12, 28, 64, 76, 83, 155, 226, 250
VZV infection is the most common viral complication among patients with RA, particularly among those receiving high doses of methotrexate. Extension is usually confined to a metamera and rarely disseminates. Considering the age and underlying condition of the patients, antiviral therapy is
BACTERIAL INFECTIONS
There is no evidence that support any etiologic role of bacterial infections in the origin of RA. Patients with RA may suffer diverse bacterial infections, but patients with septic arthritis are the only ones specifically related to this underlying condition and the authors will review them in detail. The remaining bacterial infections behave as in other population groups and the authors will only mention some relevant details.65, 117, 125, 132, 151, 160, 227, 252, 270
Neither tuberculosis nor
FUNGAL INFECTIONS IN RA
Fungal infection in RA patients is promoted by methotrexate and corticosteroids.26, 83, 155, 160, 207, 226, 228, 248 Two thirds of the described cases presented in periods of intense lymphopenia (related to the RA itself or to the use of steroids or methotrexate). It usually has an abrupt onset with high fever, dry cough, and severe respiratory failure. Chest radiograph may show an interstitial focal or diffuse pattern that may be confused with methotrexate pneumonitis.115, 231 Differential
PARASITIC INFECTIONS
There is no evidence of a particular relationship between RA and parasitic diseases. There are some reports describing, for example, Strongyloides stercoralis infection57 or the reactivation of cutaneous leishmaniasis.266
MISCELLANEOUS
Patients with RA may have fever caused by the progression of the disease, although on most occasions it does not fulfill the criteria of fever of unknown origin. When this happens, an infectious etiology has to be excluded before assigning it to the underlying condition.44, 265
Respiratory tract infections are among the most common in this group of patients and may have substantial morbidity and mortality. It is important to remember that these patients should receive the influenza vaccine every
SEPTIC ARTHRITIS
Since 1958 it has been known that joint infections are more common in patients with RA than in the general population.50, 96, 121, 141, 265 There are many reasons for this situation including the deficit in vascular flow of the joints, deficient polymorphonuclear phagocytosis in the damaged joint, the absence of C3 receptors on the cellular surface, and the increased bacterial inflow into the joint caused by the rupture of the hematoarticular barrier.34, 186 Septic arthritis is characteristic
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Address reprint requests to Emilio Bouza, MD, PhD Servicio de Microbiología y Enfermedades Infecciosas-VIH Hospital General Universitario Gregorio Marañón Dr. Esquerdo 46 28007 Madrid Spain e-mail: [email protected]
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Clinical Microbiology and Infectious Disease Service, Hospital General Universitario Gregorio Marañón, University of Madrid, Madrid, Spain