Infections in Vasculitis: Can We Create an Epidemic of Change?

In the article entitled “Prevalence, Predictors, and Prognosis of Serious Infections in Takayasu Arteritis: A Cohort Study” by Misra and colleagues in this issue of The Journal of Rheumatology, the authors examine the incidence of serious infections in a Takayasu arteritis (TA) patient cohort; analyze associated demographic, clinical, angiographic, and treatment-related factors; and evaluate their impact on serious infections and mortality in TA.¹ They found that serious infections in patients with TA were prevalent, occurring in one-sixth of their cohort, with pneumonia (38%) and tuberculosis (TB; 24%) as the most common infections identified.¹ These infections were associated with active disease and the use of, and number of, immunosuppressive therapies. Further, patients with a history of any serious infection were at an increased risk of death. Given these findings, the authors propose that future research directions should include serious infection in the damage index for patients with TA.

Other cohort studies confirm the frequency of infections, including that of Mycobacterium tuberculosis, as significant comorbidities in TA. The prevalence of TB infections in TA is likely skewed, by both the increased prevalence of TA in TB-endemic regions and the purported association between mycobacterial infection and the development of TA. However, a metaanalysis of 30 studies including patients from Southeast Asia, Africa, Western Pacific, the Americas, and the European regions demonstrated an average prevalence of TB infection of 31.27% in TA, ranging from 16.9% to 63.3%, highlighting that TB is a tangible threat to patients with TA worldwide.² However, TB is not the sole infectious threat to patients with TA. In 1994, Kerr et al reported serious infections requiring hospitalization in 14.5% in their National Institutes of Health cohort of 60 patients with TA, with herpes zoster as the most commonly identified pathogen.³ Jagtap and colleagues also reported serious infections as a leading cause of death (hazard ratio of 5.43) in a cohort of 224 patients with TA.⁴

The heightened risk of infection and mortality in vasculitis extends beyond patients with TA. Patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) are particularly vulnerable, with a large cohort study of 535 patients demonstrating that infection was responsible for 48% of deaths in the first year following diagnosis, and 20% thereafter.⁵ Infections were also frequent in the Rituximab in ANCA-Associated Vasculitis (RAVE) trial (36% rituximab group, 27% cyclophosphamide group) and in the Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis (PEXIVAS) trial (39% of patients receiving plasma exchange [PLEX], 32% of patients without PLEX).^6,7 Similarly, patients with giant cell arteritis (GCA) were reported to have frequent infections (25% in a Medicare cohort), with severe infections most common in the first year following diagnosis, and increased infection-related mortality when compared to controls.⁸ The underlying theme of increased infection risk and mortality raised by Misra and colleagues¹ rightfully demands our attention as it reaches beyond TA, adversely affecting far more patients with vasculitis.

There are several key factors that confer a higher risk of infection in patients with vasculitis, including disease-induced immune dysregulation, increased systemic inflammation, tissue damage and dysfunction, and immunosuppressive therapy. Immunologic changes identified in vasculitides include alteration of monocyte and macrophage activity, functional modifications of dendritic cells, diminished or altered immune cell activity, prolonged cell activation (leading to downregulation or cellular exhaustion), and impaired neutrophil extracellular trap degradation.^9,10 Inflammation and damage of the vessel wall results in reduced perfusion to tissues and organs, with development of ischemia, providing a more direct pathway for microbial endothelial cell invasion. Further, patients with vasculitis can develop reactivation of latent herpes viruses and other infections, which can further worsen both immune dysfunction and vascular damage, creating a vicious cycle.

With an impaired immune system, patients with vasculitis are inherently at higher risk of infection that is further exacerbated by immunosuppressive therapy. The use of glucocorticoids alone suppresses both innate and acquired immunity, enacts transcriptional and posttranslational effects that decrease cytokine expression, and diminishes leukocyte trafficking.¹¹ The consequences of this are reflected in a multicenter cohort study in which patients with GCA receiving prednisone greater than 10 mg per day after 12 months were 4.6 times more likely to have infection-associated mortality.¹² Further, treatment with anti–tumor necrosis factor therapy is associated with a markedly increased risk of TB in other immunosuppressed cohorts, with relative risks reported as high as 29 times for adalimumab and 18.6 times for infliximab in patients with inflammatory bowel disease; there is also an increased risk for other serious and opportunistic infections (OIs).¹³ A repeated theme of increased rates of serious infections and associated mortality can be seen as we increase the intensity of immunosuppression, even without examining combined immunosuppressive regimens, which are often used in the management of vasculitis.

It is frustrating that this widely recognized comorbidity continues to run rampant in our patients without any generally accepted, protocolized preventative measures. The 2021 American College of Rheumatology (ACR) guidelines for the management of AAV highlight one of the major roadblocks when addressing whether Pneumocystis jiroveci pneumonia prophylaxis should be used for patients receiving cyclophosphamide or rituximab, noting that this recommendation remains conditional “given the lack of moderate- or high-quality evidence.”¹⁴ Likewise, vaccination practices are inconsistent, with changing recommendations, timing with immunosuppression, new vaccine types, and disinformation, all of which affect both patient and medical community beliefs and often derailing the effective use of this protective measure. We need to consider where and how to make an impact on this devastating comorbidity. To develop common practices for patients with different diseases and varying therapies, with each patient having their own distinct immunologic aberrations, can seem a herculean task. However, perhaps all is not lost if we can learn from others’ successes to help us find our own way.

Pneumocystis, toxoplasma, and Mycobacterium avium complex were the first OIs reported in patients with AIDS and put the devastating consequences of a compromised immune system in the spotlight. Antimicrobial prophylaxis decreased the incidence of OIs, with improved survival of people with HIV, even prior to the development of antiretroviral therapies. This treatment is still the standard of care and a cost-effective strategy for improving and prolonging the lives of people with HIV.¹⁵

Similarly, in both solid and liquid organ transplantation, the use of antimicrobial chemoprophylaxis against both usual and OI pathogens is standard of care and tailored to the recipient’s risk and nature of the transplantation. For these patients, use of either a preemptive strategy (eg, monitoring for cytomegalovirus reactivation with planned intervention), universal prophylaxis, or a mixed approach is used. Clinical trials and metaanalyses have revealed that using antimicrobial prophylaxis in transplant patients results in reduced fever events, fewer infections, decreased infection-related mortality, and in some studies, reduction of all-cause mortality.^16,17 Additionally, many centers have protocolized and standardized the care for patients pretransplant to receive required standard vaccinations to prevent incident and severe infections post transplant.

Notably, prevention in these high-risk groups also extends beyond the use of chemoprophylaxis and vaccination protocols to include detailed infection risk screening procedures and standardized measures of infection risk reduction, both at home and in the healthcare setting. Routine risk mitigation recommendations include detailed advice about hand washing, pet and other animal exposure, soil exposure, occupational risks, potentially contaminated water, and travel precautions.¹⁷ Further, with the frequent use of combined immunosuppressive therapy, the increased risk of serious infections, infection-associated mortality, and risk of OIs in patients with vasculitis raise the question of whether their care should routinely include the expertise of transplant infectious disease physicians when serious infections are suspected or identified.

For those who wonder if it is catastrophizing to characterize patients with vasculitis as having similar infection risk as transplant patients, it is worth noting that reported infection-related mortality in both heart (32%) and lung (35%) transplant patients during the first year following transplant is lower than that of patients with AAV in the first year following diagnosis (48%).^5,18 Nevertheless, it is clear that the risk between individual patients, and even between different diseases, is not uniform, which adds to the complexity and challenge of this issue. However, starting with fully using the tools we have readily available that are beneficial in lowering infection risk in other immunocompromised populations seems a reasonable place to initiate our efforts to protect our own.

One essential measure of preventative care in patients with vasculitis is vaccination. Pneumococcal, seasonal influenza, varicella zoster, and coronavirus disease 2019 (COVID-19) vaccinations are recommended in the current ACR and US Centers for Disease Control and Prevention guidelines, with additional information provided regarding timing and immunosuppressive therapies.^19,20 Unfortunately, these recommendations are not reflected in current vaccination rates. The vaccination rates for pneumococcal vaccination in an autoimmune disease French cohort study were dismally low, where only 29% of patients received the complete series.²¹ Intriguingly, a survey of Canadian rheumatology patients found that patients with vasculitis were more likely than other patients with rheumatic disease to decline vaccination against COVID-19, with concerns about safety, vaccine components, and the possibility of contracting COVID-19 infection from the vaccine as reasons for deferring vaccination.²² Notably, only 50% of vaccine-hesitant patients with vasculitis reported discussing COVID-19 vaccines with their healthcare providers, and merely 40% felt that their healthcare team could adequately address their questions. This implies that communication with patients about the rationale and safety of vaccination, and an open dialogue about common vaccine misinformation and misunderstandings, may be an initial means of affecting vaccine hesitancy and underuse.

Advances in the monitoring of immune function occurring in the transplantation realm could also be adapted to assess and help diminish infection risk in patients with vasculitis. Some of the tools under study as biomarkers of immune function in transplantation include measuring adenosine triphosphate production in activated lymphocytes (ImmunKnow immune cell function assay; Eurofins Viracor); soluble CD30, a transmembrane glycoprotein that engages in regulation of the Th1 and Th2 response and T cell memory; and extracellular vesicles, which are particles released by cells that have the potential to act as physiologic mediators.²³ Torque teno virus, a nonpathogenic anellovirus, is under study as a biomarker for monitoring the immune response in transplant patients to identify both rejection and infection risk; a small study of select patients with AAV from the RAVE trial demonstrated an association between levels of viremia and relapse.^23,24 A more comprehensive understanding of the immunopathology and magnitude of immunosuppression in patients with vasculitis could prove an important initial step toward identifying which patients might benefit from antimicrobial prophylaxis and where initial studies to assess potential benefit should begin.

It is opportune that Misra and colleagues revisit the role of infections as an important morbidity and mortality risk in their TA cohort,¹ reminding us that we have much work to do in this area that potentially affects not only patients with TA but all patients with vasculitis. Although this is a challenging proposition, the successes in infection reduction in other high-risk populations provide hope. We can adapt and enact infection prevention strategies, using current methods while continuing to explore emerging technologies, to make headway against this pervasive adversary, with our goal mirroring the perspective of Sun Tzu: “The greatest victory is that which requires no battle.”²⁵

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