It is obvious that immunosuppressive medication is a major risk factor for infections 38. A high GC dose (often defined as more than 30 mg per day prednisolone-equivalent), especially in the form of intravenous methylprednisolone, is a significant risk factor 139. With respect to common clinical experience, its importance seems to be underestimated in clinical trials because, for example, the cumulative GC dose is not usually stated. In a study on giant cell arteritis (GCA) solely treated with GCs, 86% of the patients experienced severe GC-related adverse events, including severe infections in 31% 40. Schmidt and colleagues 41 reported a relative risk of severe infections - that is, infections leading to hospitalisation - of 2.44 in the first 6 months of GC treatment in a large GCA trial and increased infection-related mortality. Rising awareness of GC complications, including infections, makes GC sparing an increasingly important aim. According to the European League Against Rheumatism (EULAR) recommendations for conducting clinical trials in PSV, protocols should be designed to reduce patients' total exposure to GCs, which includes recording cumulative GC doses and the use of GC-sparing drugs like methotrexate (MTX) 42.

Although some trials using cyclophosphamide (Cyc) report very low rates of infectious complications 1733, Cyc use in SVV is associated with higher rates of infections and fatalities than the use of medium potent immunosuppressants such as MTX, azathioprine or leflunomide 222426. Among the latter no differences concerning rates and types of infections can be derived from the available data. When analysing infectious complications, it has to been taken into account that treatment changes over time. For example, the CYCAZAREM-trial demonstrated that oral Cyc could safely be substituted by azathioprine after achieving remission, leading to much lower cumulative Cyc doses 35. The use of Campath-1H, a monoclonal antibody to CD52 that leads to lymphocyte depletion and profound neutropenia, was associated with high rates of infectious complications, as was expected from experience with its use in haematology 32. A clear association of drugs with specific types of infections, as is known for tuberculosis (TB) and anti-TNF-α agents, can not be derived from the still limited data from PSV trials.

As shown in Table 1, there are large differences regarding the forms of PSV and their infection-related mortality. Infections and mortality from infectious complications are much more prevalent in SVV than in large vessel vasculitis. In GCA trials, mortality ranged from 0 to 0.03 deaths per patient year and infections caused 0 to 33% of these deaths 4567891011. In SVV this range was 0 to 0.26 deaths per patient year and infections were involved in 0 to 100% of the fatal events 1171819202122232425262728293031323334353637.

Interestingly, in most published clinical trials in GCA, PCP prophylaxis was not used. Despite the fact that high doses of GCs are a major risk factor for the development of PCP, no case of PCP has been reported within these trials 45678910. In contrast, patients with antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV), especially those with Wegener's granulomatosis (WG), are at high risk for PCP that can not be attributed only to medication 181920212223242526272829. There is evidence that at least some entities within the group of PSV confer an altered function of the immune defence per se. In WG, for instance, the granulomatous inflammation of the upper respiratory tract leads to destruction of the barrier function of the surfaces, possibly allowing for invasion of pathogens 43. It may also be possible that a primary barrier deficiency not only promotes infections but has a role in the aetiology of the disease itself 44.

In PSV, and especially in SVV, the therapeutic approach usually consists of an induction of remission and a maintenance phase (for review, see 45). For induction, more aggressive regimens, including Cyc and higher GC doses, are utilised. Furthermore, in SVV the selection of drugs depends on the stage of the disease: in the localised and early systemic stage - that is, disease without threatened vital organ function - induction of remission is usually attempted with medium potent immunosuppressants such as MTX, whereas in generalised and severe disease - that is, with threatened vital organ function or organ failure, respectively-Cyc is used.

In SVV the induction of the remission period is the most vulnerable phase concerning infections and mortality. From studies assessing only maintenance of remission, published mortality rates ranged from 0 to 0.01 deaths per patient year and infections did not significantly contribute to those fatalities 182123272830. In contrast, trials on induction of remission in SVV reported mortality rates up to 0.26 per patient year. In those trials infections were responsible for the fatal events in up to 100%, and about 50% of deaths, on average, were due to infections 117202224262931323334353637. Accordingly, mortality was higher in study populations with more severe disease. The highest reported rate was in SVV patients who presented initially with organ (renal) failure 1. But even in this population, in which one might expect a higher contribution of uncontrolled disease to the death rate, infections are involved in more than 50% of the fatal outcomes.

In PSV trials Staphylococcus aureus is the isolate for which fatal outcome has been reported most frequently. As demonstrated in surgical patients and patients on dialysis, prophylactic topical treatment with mupirocin ointment for nasal carriers of S. aureus leads to a significant reduction in the rate of infections with this agent (relative risk 0.55 according to 46). Especially in WG, the incidence of nasal colonisation with S. aureus is higher than in controls and chronic carriage is associated with higher relapse rates 47. In addition, relapses are often anteceded by infection, mainly of the upper respiratory tract 4849. Furthermore, it is well documented that trimethoprim/sulfamethoxazole (T/S) treatment reduces the rate of relapse and is able to induce remission in some WG patients, especially those with localised disease 2850. It is not clear whether this effect is achieved by its antibiotic or its immunomodulatory properties. Although its primary end point was relapse rates, the study by Stegeman and colleagues 28 clearly demonstrated a reduction in respiratory-tract as well as non-respiratory-tract infections using T/S in WG patients in remission. This study can be regarded as the only large scale trial of anti-infective prophylaxis in vasculitis.

As topical mupirocin does not cause serious adverse events 46, it is used in some vasculitis centres during the high risk phase of induction of remission in SVV (seven subsequent days three times daily per month). One concern, however, is that with mupirocin there is an increase in infections other than those due to S. aureus 46. For reasons of possible development of resistance as well as compliance problems, long-term use should be avoided.

Besides topical treatment, systemic antibiotics are another option for AIP, although they have not been used in PSV remission induction trials so far. From randomised controlled trials using, for example, levofloxacine in patients with malignancies during chemotherapy-induced neutropenia (<500 neutrophils per microlitre), it is known that a reduction in the incidence of neutropenic fever and hospitalisation can be achieved 23. An effect on mortality has not been demonstrated and there are concerns regarding the long-term outcome of such interventions on microbial resistance in the community. As the treatment of PSV using standard protocols does not usually lead to prolonged neutropenia and the effectiveness of chemoprophylaxis with, for example, levofloxacine with regard to mortality has not been proven in patients treated with more intense chemotherapy, there is no standard setting for which the use of systemic antibacterial prophylaxis can be recommended. Although clear evidence for its use during induction of remission - apart from PCP-prophylaxis - is missing, T/S has proven its ability to reduce bacterial infections in patients with WG 28 and, therefore, might be considered in high-risk patients.

Other antibiotics, such as levofloxacine, might only be considered in refractory heavily pre-treated PSV patients undergoing salvage therapy with drugs known to induce severe neutropenia - for example, campath-1H.

CMV is a herpesvirus that leads to latent infection. Its prevalence ranges between 60 and 100%, depending on the geographic area 61. CMV reactivation leads to a high burden of morbidity and mortality in immunocompromised persons, an interrelation best studied in transplantation medicine 62. The spectrum of manifestations ranges from non-symptomatic infection to life-threatening disease, for example, pneumonitis. The scale of this problem in rheumatology and especially in PSV patients is insufficiently defined but appears to be less severe in most cases. In vasculitis patients leucopenia is the most frequent manifestation. However, in clinical trials some cases of CMV illness have been described with a relatively high proportion of fatal outcomes 202225. Large scale underreporting must be assumed, since until recent years reliable detection methods have been missing and the awareness of this problem appears to be still low. Mori and colleagues 63 found a high incidence of CMV reactivation in CMV-seropositive patients with connective tissue disease undergoing immuno-suppressive therapy. A recent study by Takizawa and colleagues 39 suggests that GC use, especially in the form of pulsed methylprednisolone as well as other immuno-suppressants, primarily Cyc, are the major risks factors for CMV reactivation in rheumatic diseases. In PSV, and especially in WG, CMV reactivation is an important differential diagnosis if neutropenia occurs.

In solid organ transplant recipients prophylaxis with, for example, ganciclovir or valganciclovir reduces CMV disease 64. If CMV disease occurs in severely compromised patients with rheumatic diseases, anti-viral therapy might be without benefit as reported by Takizawa and colleagues 39 in a cohort of 85 patients. As CMV itself leads to further immunosuppression, fatal co-infections are promoted 39. Taken together, these are arguments in favour of anti-viral prophylaxis in CMV-seropositive PSV patients undergoing intense immunosuppression. However, as data from clinical trials are missing, no evidence-based recommendation as to which patients should be introduced to prophylaxis can be given. In praxi prophylaxis (valganaciclovir 900 mg once daily) might be considered only in severely ill PSV patients who need high dose methylprednisolone pulses or Cyc, especially if they had experienced earlier CMV reactivations. An alternative to this, as well as for other latently infected patients who need intense immunosuppression, is the preemptive approach, which also has been proven to be effective in organ-transplant recipients 65. This requires quantitative monitoring of CMV - for example, by measurement of early antigen (pp65)-positive cells. Takizawa and colleagues 39 suggested a threshold of 5.6 pp65 positive cells per 10⁵ polymorphonuclear cells. Measurement of early antigen is increasingly replaced by quantitative CMV-PCR, which is currently the method of first choice.

Varicella zoster virus (VZV) reactivation leads to herpes zoster (HZ). Whereas age is the most important risk factor for the development of HZ 66, autoimmune diseases and especially immunosuppressive therapy with Cyc and GCs further increases the probability of reactivation 67. Several PSV trials report relatively high numbers of VZV reactivation and HZ 28. However, underreporting of this usually non-life-threatening condition is likely. HZ causes substantial morbidity, especially when post-herpetic neuralgia develops, which is the case in up to 20% of the elderly population 68.

Despite these facts, no trial in PSV has included VZV prophylaxis to our knowledge, although it is feasible and effective at least in patients receiving haematopoietic stem cell transplantation using, for example, aciclovir (2 × 800 mg per day) or valaciclovir 69. The reason for not administering VZV prophylaxis in PSV may be the high potential for drug interactions and adverse events, especially in patients with renal impairment and the non-life- or organ-threatening nature of HZ in this population. In general, VZV prophylaxis is not recommended in PSV patients. It might be considered only in selected patients who have experienced several VZV reactivations and have an ongoing need for intense immunosuppression. More importantly, patients should be trained to recognise the early signs and symptoms of HZ to enable the immediate start of anti-viral therapy in the case of possible HZ.

Vaccination to avoid HZ is available and effective 70. In the US it is recommended by the Advisory Committee on Immunization Practices for all persons older than 60 years 70 but it is not recommended in patients under immuno-suppressive medication 71. Whether patients in remission from PSV under mild immunosuppression may benefit from vaccination warrants further investigation.

Invasive fungal infections (other than PCP) are rare in PSV. Risk factors for the development of pulmonary Aspergillus sp. infections are prolonged episodes of neutropenia and prolonged use of high-dose GCs 72. Few cases of invasive Aspergillus infections and fatalities in PSV have been reported 132224.

There is generally no indication for the prophylactic use of systemic anti-mycotics in PSV but aspergillosis should be considered as a differential diagnosis in patients if fever of unknown origin does not resolve under a calculated antibiotic therapy.

In contrast to invasive aspergillosis, Candida infections of mucosal membranes are a frequent complication of GC treatment, although leading to invasive candidiasis only very rarely. Nonetheless, oral candidiasis or candida esophagitis are painful and might hinder oral nutrition. In critically ill patients and solid organ transplant recipients prophylaxis using fluconazole is effective in avoiding invasive candidiasis 7374. Using topical non-absorbable antifungal prophylaxis in immunocompetent critically ill patients leads also to a significant reduction in fungal (mainly non-invasive) infections 75. According to the BSR, prophylaxis with nystatin, amphotericin or fluconazole should be considered in all AAV patients receiving high-dose immunosuppressive therapy 57.

In praxi amphotericin suspension in all patients under long term GC medication with a dose of >15 mg prednisolone per day can be recommended because it is effective, non-absorbable and associated, therefore, with very few side effects. According to a meta-analysis, the non-absorbable nystatin is not more effective in avoiding fungal colonisation than placebo and can not be recommended 76. Additionally, all patients should be instructed to perform daily self-inspections of the mouth in order to detect mucosal candidiasis early.