Systemic lupus erythematosus and infections

Introduction

Infections represent a significant contributor to morbidity and mortality among patients with systemic lupus erythematosus (SLE). Inherent dysfunction in innate and adaptive immune responses as well as chronic immunosuppressive treatment begets vulnerability to acute and chronic infections. Patients with SLE may also face separate challenges related to accrued end-organ damage, functional hyposplenism, and reticuloendothelial system flaws. These further hamper the ability to defend against infections. Conversely, infections may trigger lupus flares, so that clinicians are frequently faced with the challenge of diagnosing active lupus, infection, or the coexistence of both. Thus, the diagnostic approach to the infected SLE patient must be thoughtful and thorough. In addition, vigilance is warranted regarding preventive strategies for SLE patients to mitigate the risk of infection.

Epidemiology of SLE infections

The largest cited epidemiologic lupus studies examining rates of deaths due to infection have found wide variation, ranging from 5% to 67% in larger cohorts ( Table 47.1 ). Most studies examining the incidence of infection and related mortality among patients with lupus have used inpatient data. This likely presents a skewed perspective as inpatients have higher disease burden and encounter nosocomial pathogens. The largest population-based study comparing infection-related mortality between SLE and non-SLE revealed that the highest mortality rates were among patients with opportunistic infections and those with mechanical ventilation requirements for pneumonia or sepsis. The trend in hospitalization rates for serious infections in SLE increased substantially between 1996 and 2011, nearly 12 times higher than non-SLE patients.

A recently published nationwide study looking at United States Medicaid data from 2000-2006 examined inpatient mortality rates and deaths within 30 days of discharge among SLE patients hospitalized for infections. In this cohort of 5078 SLE patients, 778 (15.3%) died prior to the end of the study period and of those patients, 354 (45.5%) died within 30 days of having been inpatient for an infection. A separate finding of this study revealed that those patients with lupus nephritis had twice the incidence rates of hospitalized infections versus non-nephritis SLE patients and higher overall mortality versus the non-nephritis SLE patients. There were also significantly higher risks of infections among males, older aged patients, and those with lower socioeconomic status. Black and Native American patients also had higher incidence rates of infections versus white patients in this analysis. Baseline hydroxychloroquine use conferred a reduced infection risk and glucocorticoid users had an increased risk of infections compared to never users.

While SLE is a chronic illness with a lifelong risk of infection, the specific causes of death vary by age and duration of disease. Deaths due to complications of SLE or infection are more common during the first 5 years of disease while deaths due to cardiac complications and thrombotic events are more common over subsequent decades. Infections remain the most frequent cause of death within the first year of SLE onset. A study of SLE with primary disease onset after age 50 found that infection was the major cause of death in this subgroup.

Geography also appears to influence the overall risk of death from infection among SLE populations around the world. Wang et al. published a large meta-analysis in 2015 that found that infection still remains the leading cause of death in China. The leading cause of death in SLE in France between 2000 and 2009 was cardiovascular disease, then malignancy, followed by infection. Likewise, contemporary Canadian, United Kingdom and US studies have shown cardiovascular disease to be the leading mortality cause ahead of renal complications and infection-related deaths in lupus populations.

Navarro-Zarza et al. found that among 473 hospitalized patients with SLE with no symptoms or signs of infection at the time of admission, 12.5% developed a nosocomial infection. In this study, length of hospital stay, higher SLEDAI activity scores, and immunosuppressive medications were significant predictors of nosocomial infection. Other studies have reported higher rates of bacterial sepsis among SLE patients with renal failure. The degree of hypocomplementemia and lymphopenia in patients with SLE has also emerged as an important predictor of significant infections, particularly in the early stages of SLE.

Certain infections can act as triggers for SLE exacerbations and may contribute to the initial development of autoimmunity in SLE. Pathogens with similar amino acid sequences or antigenic structures that are nearly identical to native molecules have been posited to promote autoantibody production and clinical manifestations of SLE as the result of cross-reactive antibodies or molecular mimicry. For instance, there have been several homologous amino acid sequences noted to exist between Epstein–Barr virus (EBV) nuclear antigens and nuclear autoantigens found among patients with SLE. Serologic evidence of EBV infection has also been shown to be significantly higher in SLE patients compared with healthy matched controls. Other studies have proposed a relationship between induction of SLE and infection with herpes simplex virus, human herpes virus 8, parvovirus B19, or cytomegalovirus, although additional studies are needed to establish a pathogenic role for these infections. Superantigens released from mycoplasma species and other common infections have been shown to activate T lymphocytes and B lymphocytes, leading to exacerbations of existing SLE. Gram-negative lipopolysaccharide associated with certain bacterial infections can lead to polyclonal B-cell activation and worsening of disease SLE disease activity.