In Vasculitis, Beware of Infection Save

Risks of infection were strikingly high among patients with antineutrophil cytoplasmic antibody-associated (ANCA) vasculitis, which may relate to both the disease and its treatment, Scottish researchers found.

Compared with matched controls from the general population, the risk of laboratory-confirmed infection was seven times higher among ANCA-associated vasculitis patients, with an incidence rate ratio (IRR) of 7.3 (95% CI 5.6-9.6), according to Neil Basu, MBChB, PhD, of the University of Glasgow's Institute of Infection, Immunity, and Inflammation, and colleagues.

In addition, the risk of severe infection requiring hospitalization was more than four times higher (IRR 4.4, 95% CI 3.3-5.7) and the likelihood of having been given an antibiotic prescription in primary care was doubled (IRR 2.2, 95% CI 1.9-2.6), the researchers reported online in Rheumatology.

The ANCA-associated vasculitides are autoimmune disorders including granulomatosis with polyangiitis, microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis. Five-year survival has been estimated at 80%, with considerable morbidity and mortality associated with drug toxicity and infections related to immunosuppression.

However, estimates of infection rates in ANCA-associated vasculitis have been wide, ranging from only 6% to as high as 67%, and most often have been limited to cases involving hospitalization.

To provide more details and more clearly quantify the risks of infection in this patient population, Basu's group analyzed data from National Health Services Scotland for the years 2008 to 2017. Each patient with ANCA-associated vasculitis was matched by age, sex, and geography with up to five healthy controls, giving a sample of 379 patients and 1,859 controls, all followed for a median of 3.5 years.

Slightly more than half were men, and the median age at baseline was 62. The most common subtype of vasculitis was granulomatosis with polyangiitis.

During the course of the study, 55.4% of patients had one or more laboratory-confirmed infection, 35.6% had a severe infection, and 74.6% were given an antibiotic prescription in primary care. There were 35 deaths, although none had the primary cause of death listed as infection.

Laboratory-confirmed infections were reported most commonly during the first year of follow-up, when the IRR was 14.3 (95% CI 9.9-20.7) and particularly in the first 30 days (IRR 63.1, 95% CI 29.2-136).

Serious infections had a similar pattern, being highest in the first 30 days (IRR 10.6, 95% CI 4-28) and remaining high at 1 year (IRR 6.6, 95% CI 4.1-10.5). Although the rates declined thereafter, patients continued to have more infections than controls throughout the study period. By year 8 of follow-up, the IRRs for laboratory-confirmed and serious infections were 3.7 (95% CI 1.6-8.9) and 4.2 (95% CI 1.3-13.6), respectively, the researchers reported.

The persisting risks for infection for several years may relate to both immunosuppressive medication use and the disease itself, as some patients continue to take powerful immunosuppressive medications for lengthy periods. "However, a large proportion of patients are completely weaned off such therapy after 2 to 5 years and it is interesting to observe similar infection risk ratios from year 3 onwards, suggesting persisting long-term immune dysfunction that may reflect chronic perturbation of the underlying disease or continued injury from past immunosuppression," Basu and colleagues wrote.

The team also looked at the types of pathogens involved, identifying 61 entities, and found that the most common sites of infection were the urinary tract, in 27%; the bloodstream, in 22.3%; and the lower respiratory tract, in 19.9%.

In both groups, the most commonly identified pathogen genus was Escherichia (16.2% of patients and 5.5% of controls) but certain pathogens were detected significantly more often among patients compared with controls:

• Herpes, IRR 12.5 (95% CI 3.7-42.6, P<0.0001)
• Candida, IRR 11.4 (95% CI 2.4-55.4, P=0.002)
• Clostridium, IRR 9.2 (95% CI 2.7-30.7, P<0.0001)
• Enterococcus, IRR 5.3 (95% CI 2.2-12.4, P<0.0001)
• Enterobacter, IRR 5.2 (95% CI 2-14, P=0.001)

The challenge of infections in patients with ANCA-associated vasculitis has been recognized in international guidelines on management, with recommendations for prophylaxis against Pneumocystis jirovecii with co-trimoxazole among patients receiving cyclophosphamide, and also for vaccinations when possible.

But because the risks remain substantially higher than for the general population, "taken together, the role of broader-spectrum antibiotic prophylaxis -- at least during the first months -- should be considered," the authors wrote.

The benefits of such an approach must be balanced against possible risks, however, the researchers cautioned, concluding: "Clinical trials are warranted to complement targeting of modifiable risk factors (e.g., corticosteroids, dosing regimens) in order to reduce this unacceptable infection burden."

A limitation of the analysis, the team said, was the possibility of surveillance bias.

Basu reported having no conflicts; one co-author reported being an employee of GlaxoSmithKline.