Common Infections in Patients Prescribed Systemic Glucocorticoids in Primary Care: A Population-Based Cohort Study

Abstract

Background

Little is known about the relative risk of common bacterial, viral, fungal, and parasitic infections in the general population of individuals exposed to systemic glucocorticoids, or about the impact of glucocorticoid exposure duration and predisposing factors on this risk.

Methods and Findings

The hazard ratios of various common infections were assessed in 275,072 adults prescribed glucocorticoids orally for ≥15 d (women: 57.8%, median age: 63 [interquartile range 48–73] y) in comparison to those not prescribed glucocorticoids. For each infection, incidence rate ratios were calculated for five durations of exposure (ranging from 15–30 d to >12 mo), and risk factors were assessed. Data were extracted from The Health Improvement Network (THIN) primary care database. When compared to those with the same underlying disease but not exposed to glucocorticoids, the adjusted hazard ratios for infections with significantly higher risk in the glucocorticoid-exposed population ranged from 2.01 (95% CI 1.83–2.19; p < 0.001) for cutaneous cellulitis to 5.84 (95% CI 5.61–6.08; p < 0.001) for lower respiratory tract infection (LRTI). There was no difference in the risk of scabies, dermatophytosis and varicella. The relative increase in risk was stable over the durations of exposure, except for LRTI and local candidiasis, for which it was much higher during the first weeks of exposure. The risks of infection increased with age and were higher in those with diabetes, in those prescribed higher glucocorticoid doses, and in those with lower plasma albumin level. Most associations were also dependent on the underlying disease. A sensitivity analysis conducted on all individuals except those with asthma or chronic obstructive pulmonary disease produced similar results. Another sensitivity analysis assessing the impact of potential unmeasured confounders such as disease severity or concomitant prescription of chemotherapy suggested that it was unlikely that adjusting for these potential confounders would have radically changed the findings. Limitations of our study include the use of electronic medical records, which could have resulted in some degree of misclassification of the infectious outcomes; a possible reporting bias, as general practitioners could be more prone to record an infection in those exposed to glucocorticoids; and a low number of events for some outcomes such as scabies or varicella, which may have led to limited statistical power.

Conclusions

The relative risk of LRTI and local candidiasis is very high during the first weeks of glucocorticoid exposure. Further studies are needed to assess whether low albumin level is a risk factor for infection by itself (e.g., by being associated with a higher free glucocorticoid fraction) or whether it reflects other underlying causes of general debilitation.

Abstract

Fardet and colleagues present a large population study assessing the risks of developing infections following glucocorticoid treatment. They describe the impact of age and other conditions such as diabetes on developing infections.

Editors’ Summary

Background

Throughout life, our immune system protects us from attack by disease-causing organisms. When a virus, bacterium, fungus, or parasite enters the human body, the immune system detects the invader and triggers a response that kills or neutralizes it. Normally, the immune system discriminates perfectly between foreign invaders and the body’s own cells and tissues, but sometimes it goes awry and begins to attack “self,” resulting in the development of an autoimmune disease such as rheumatoid arthritis (in which the immune system attacks the joints) or lupus erythematosus (in which the immune system attacks numerous tissues and organs). Immune system dysfunction is also involved in chronic inflammatory conditions. Tissue inflammation (pain, heat, redness, and swelling) is part of the normal immune response, but uncontrolled inflammation underlies sepsis (a systemic inflammatory condition that sometimes develops after a localized infection) and lung conditions such as asthma and chronic obstructive pulmonary disease.

Why Was This Study Done?

Inflammatory diseases and autoimmune diseases are often treated with glucocorticoids—drugs with immunosuppressive and anti-inflammatory properties. At any one time, more than 1% of the US and UK population is receiving systemic glucocorticoid therapy (whole-body therapy often given as a pill) to treat an autoimmune or inflammatory condition or to treat cancer or prevent organ rejection after transplantation. But, although prednisolone, dexamethasone, and other glucocorticoids are effective treatments for these conditions, long-term use of oral glucocorticoids is associated with serious side effects, including an increased infection risk. Several studies have investigated the overall risk of infection in specific populations receiving glucocorticoids, but little is known about the risk of individual common infections among people in the general population taking glucocorticoids. Here, the researchers undertake a population-based cohort study—an observational investigation that compares specific outcomes in groups (cohorts) of people from the general population with different baseline characteristics—to discover more about common infections in patients prescribed systemic glucocorticoids in primary care.

What Did the Researchers Do and Find?

Using The Health Improvement Network (THIN) primary care database, the researchers identified 275,072 adults prescribed oral glucocorticoids in the UK between 2000 and 2012, a random sample of people not prescribed glucocorticoids but with a diagnosis of the same underlying disease as the exposed individuals, and cases of infection in both cohorts. Compared to the unexposed group, the glucocorticoid-exposed group had an increased risk of three bacterial infections (septicemia, lower respiratory tract infection [LRTI], and cutaneous cellulitis), one viral infection (herpes zoster), and one fungal infection (local candidiasis) but no increased risk of varicella virus infection, dermatophytosis (a fungal infection), or scabies (a parasitic infection). The increased risk was highest for LRTI—the risk of LRTI was nearly six-fold higher in the glucocorticoid-exposed group than in the unexposed group. The relative increase in infection risk was similar whatever the duration of glucocorticoid therapy except for LRTI and local candidiasis, for which it was higher in the first few weeks of treatment. The risk of infection increased with age and was higher in people with diabetes, in people given high glucocorticoid doses, and in people with low blood albumin levels. Finally, the risks of different infections depended on the disease for which glucocorticoids were prescribed.

What Do These Findings Mean?

These findings show that the risk of several (but not all) common bacterial, viral, and fungal infections was higher among people prescribed glucocorticoids for a range of underlying diseases than among people matched for age, gender, and underlying disease who were not prescribed glucocorticoids. Notably, the relative risk of LRTI and local candidiasis was particularly high during the first weeks of glucocorticoid exposure. Several aspects of the study design may affect the accuracy of these findings. For example, the use of medical records may have resulted in some misclassification of infectious outcomes. However, the finding of a high risk of LRTI in patients prescribed systemic glucocorticoids should be considered before prescribing these drugs, particularly in patients with asthma or chronic obstructive pulmonary disease. The finding of an association between low blood albumin level and increased infection risk needs further investigation to determine whether a low albumin level is a direct risk factor for infection or a marker for other underlying causes of debilitation that increase the risk of infection, but it may be worth considering monitoring albumin level before and during glucocorticoid treatment.

Additional Information

This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1002024.

• This study is further discussed in a PLOS Medicine Perspective by Lionel Rostaing and Paolo Malvezzi

• The UK National Health Service Choices website provides information about corticosteroids (glucocorticoids are a specific type of corticosteroids)

• The Mayo Clinic has an article about the benefits and risks of corticosteroids

• Wikipedia has information on autoimmune disease, inflammatory disorders, and glucocorticoids (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)

• MedlinePlus provides links to further information about autoimmune diseases and about corticosteroids

• More information about The Health Improvement Network database of anonymized electronic medical records is available