Objective: To characterise major infectious complications and analyse potential risk factors in patients with Wegener granulomatosis (WG).
Methods: Data from 113 patients with WG (69 male) followed at least once between January 1984 and March 2006 in our internal medicine department, were analysed retrospectively.
Results: A total of 35 patients (mean (SD) age at WG diagnosis: 50.2 (13.05) years) developed 53 major infections. Infections were: bronchopneumonias (n = 19), herpes zoster recurrences (n = 9), cellulitis (n = 4), prostatitis (n = 4), spondylodiscitis and septic arthritis (n = 3), digestive tract infections (n = 2), Enterococcus faecalis or Staphylococcus aureus septicaemia (n = 2), viral hepatitis B reactivations (n = 2), post transfusion HIV infection with fatal cerebral toxoplasmosis, oesophageal candidiasis, disseminated herpes simplex and cytomegalovirus infection, cytomegalovirus retinitis, herpetic keratitis, herpetic stomatitis, Serratia sp. node suppuration and fever resolving under broad spectrum antibiotics (n = 1 each). Half of the major infectious episodes occurred within 3 years after WG diagnosis. Eight (7%) patients died, with two (2%) infection-related deaths. Patients diagnosed with WG before 1996 had a significantly higher rate of infection than those diagnosed later (48% vs 24%, p = 0.02). Cyclophosphamide and corticosteroids were independently associated with significantly higher risk of major infection (p<0.05 and <0.001, respectively). All patients treated since 1993 received antipneumocystosis prophylaxis.
Conclusion: Cyclophosphamide and corticosteroids were associated with higher risk of infection. Despite systematic cotrimoxazole prophylaxis, major infections, mostly bronchopneumonias and herpes zoster recurrences, were still common in the course of WG.
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Wegener granulomatosis (WG) is a necrotising granulomatous vasculitis affecting small-sized vessels. Before the 1970s, the 1-year mortality rate of systemic WG was 90%.1 Corticosteroids (CS) and cytotoxic agents, mainly cyclophosphamide (CYC), have dramatically improved the outcome, but may favour the development of major infections, such as septicaemia, Pneumocystis jiroveci pneumonia (PJP) or herpes zoster reactivation.1–5 Despite systematic PJP prophylaxis with cotrimoxazole and lower treatment intensity, infectious episodes remain a major concern. Progressive reduction of the number and severity of infections has been obtained by switching oral CYC to intravenous pulse administration and by shortening CYC induction to 3–6 months, followed by a less toxic maintenance regimen comprising low-dose CS and azathioprine (AZA), methotrexate (MTX) or other immunosuppressant(s).6–8
To date, the burden of major infections in patients with WG has not been specifically addressed.1 2 6 7 9–12 Therefore, the main objectives of this study were to describe the clinical characteristics of major infectious episodes occurring in patients with WG, to evaluate the relationship between them and various treatment regimens, and to identify possible risk factors associated with these infections in a cohort of patients with WG followed in a single centre.
PATIENTS AND METHODS
We retrospectively reviewed the medical charts of all patients over 12 years old who met the American College of Rheumatology (ACR) classification criteria for WG and were followed in our Department of Internal Medicine between 1 January 1984 and 30 March 2006. Our department, part of the Paris University, was located until September 2003 at Avicenne Hospital in Bobigny, North East of Paris and is now at Cochin Hospital, Paris, and is the national referral centre for necrotising vasculitides. To improve the homogeneity of the population to be studied, we considered only patients followed in our department. Major infectious episodes were defined as those requiring hospitalisation or treatment with intravenous and/or prolonged antibiotics. Additionally, herpes zoster recurrences were also considered as major infections as they reflected consistent WG treatment-induced immunosuppression. Mild infections, such as rhinitis, cystitis or bronchitis, were not considered.
All patients diagnosed before 1996 received induction therapy with daily high-dose CS (1 mg/kg for 6 weeks, which was then slowly tapered) and daily oral CYC (2 mg/kg). Since 1996, the induction regimen had been modified to intravenous CYC (0.6 g/m2 on days 0, 15 and 30, then 0.7 g/m2 every 3 weeks until remission) combined with oral CS (1 mg/kg for 4 weeks then quickly tapered), in accordance with international trial recommendations. 9 13 14 Administration of 1-3 methyl-prednisolone (MPS) infusions could be prescribed at treatment onset according to the severity of the WG presentation at diagnosis.
Before 1996, oral CYC was usually continued for up to 18 months to maintain first remission. Since 1996, maintenance therapy has consisted of AZA (2 mg/kg/day) or MTX (0.3 mg/kg/week) for at least 12–18 months.
Treatment of WG relapses was not codified and was chosen according to their severity and the results obtained with the previously administered agents. Relapse-induction therapy consisted of oral or intravenous CYC and, in some cases, infliximab (3–5 mg/kg), rituximab (375 mg/m2 once a week for 4 consecutive weeks), etanercept (50 mg twice a week), intravenous Ig (2 g/kg/month) and/or plasma exchanges were combined. The maintenance therapy after obtaining a new remission comprised drugs other than those used in a previous maintenance strategy. This was usually AZA, MTX, mycophenolate mofetil (MMF, 2 g/day since 2002) and, in some cases, intravenous Ig.
Once PJP had been identified as a major and frequent complication of WG, systematic prophylaxis with cotrimoxazole (400/80 mg/day) or with a pentamidine monthly aerosol for patients intolerant or allergic to cotrimoxazole was prescribed.3 Prophylaxis was withdrawn after immunosuppressants were stopped and lymphocyte counts normalised. Patients with previously untreated latent tuberculosis received a complete 6-month regimen. No specific recommendations concerning vaccination against Streptococcus pneumoniae or influenza were made.
Clinical, biological and immunological data were collected in a database at WG diagnosis, during infectious episodes and at the last visit taken into consideration for this study. CYC, CS, MMF, AZA and MTX cumulative doses were calculated at the time of infection and at the end of the follow-up using the method described by Stuck et al (ie, mean daily dose multiplied by the number of days of treatment).15 Total cumulative doses were expressed per year of follow-up. Additional factors favouring infections were also collected (ie, diabetes, renal insufficiency, alcoholism or cancers).
To identify risk factors potentially associated with major infections, we compared patients who developed at least one episode during the follow-up to those with no such events. The analysed variables included the sex, age at WG diagnosis, presence of additional factors favouring infection, WG organ involvement, “ever use” of each of the main immunosuppressive drugs (CYC, CS, AZA, MTX, MMF) and the cumulated doses of cytotoxic agents and CS (IV, oral >20 mg/day and oral ⩽20 mg/day) expressed per year of follow-up. Similar comparisons were conducted between patients diagnosed before and in/after 1996, to assess the potential impact of therapeutic changes on the development of major infections. To evaluate the possible infectious risk associated with WG induction regimen, the characteristics of early-occurring and late-occurring infectious episodes, defined using the median duration of WG follow-up at the time the infection occurred (irrespective of the year of their occurrence; ie, before or during and after 1996) were compared. A two-sample Student t test was used to compare quantitative variables (mean (SD)), while the Fisher exact test was applied to compare the distributions of categorical variables for the groups. All statistical analyses were conducted by using SPSS V. 13.0 (SPSS, Chicago, Illinois, USA) and the R software environment for statistical computing (available at http://www.r-project.org/).16
Baseline characteristics of the study population
The main demographic and clinical characteristics of the 113 patients are summarised in table 1. The duration of follow-up post WG diagnosis corresponded to 758 patient-years. Mean baseline creatinine level at WG diagnosis was 131 (168) µmol/litre.
Induction and maintenance treatments
Induction therapy comprised CS (n = 110, 97%) and oral (n = 16, 14%) or intravenous CYC (n = 92, 81%). Two patients with lung involvement were referred to our centre after remission had been obtained with CS alone; they did not receive CYC until subsequent relapses. Three patients had limited WG consisting of isolated rhinitis and/or sinusitis and were treated with cotrimoxazole alone (1600 mg/day). Maintenance therapy included oral CYC (n = 13, 12%), AZA (n = 64, 57%) and MTX (n = 29, 26%). Two patients received no maintenance therapy: one died during the induction phase, the other was still under induction therapy at the time her file was included in this study.
A total of 104 patients took a PJP prophylaxis and 4 were treated for latent tuberculosis.
The 52 (46%) patients who experienced ⩾1 relapse were treated with 1 or several drugs, sometimes in combination: intravenous CYC (n = 20, 18%), oral CYC (n = 45, 40%), intravenous Ig (n = 18, 16%), infliximab (n = 10, 9%), rituximab (n = 9, 8%) and plasma exchanges (n = 8, 7%). WG maintenance treatments after relapse included MTX (n = 15, 13%), AZA (n = 24, 21%), MMF (n = 19, 17%) and etanercept (n = 2, 2%).
Additional factors potentially favouring infection
In addition to treatment-induced immunosuppression, 23 (20%) patients had at least 1 additional factor that could favour the occurrence of infections. In all, 12 patients developed either CS-induced diabetes mellitus (n = 5) or renal insufficiency requiring intermittent or chronic haemodialysis (n = 7). One patient with CS-induced diabetes mellitus also underwent post-traumatic splenectomy. The other factors were: chronic alcoholism (n = 5), pre-WG diabetes (n = 4), prostatic cancer treated with hormonotherapy and large B cell lymphoma treated with chemotherapy (n = 1 each).
Characteristics of the patients developing infectious episodes
A total of 53 major infectious episodes occurred in 35 (31%) patients, with a rate of 0.071 infections/patient-year. The median age at the time of infection was 56 years (range 18 to 80). Eight patients had multiple (up to six) major infectious episodes. Nine patients had additional factors favouring infection: haemodialysis (n = 4), CS-induced (n = 4) or pre-existing diabetes mellitus (n = 1). They experienced one (n = 4) or more (n = 5) infectious episodes. Median follow-up from WG diagnosis to a major infection was 3 years, with 21 (39.6%) episodes occurring during the first year post WG diagnosis (fig 1). A total of 11 infectious episodes occurred in 11 patients during induction therapy, 11 episodes occurred in 7 patients on maintenance therapy, 27 episodes occurred in 18 patients during treatment for relapses. Four infectious episodes, two herpes zoster and two bacterial pneumonias, were recorded after immunosuppressants had been stopped (1–3 years) (table 2.).
Cytotoxic treatments being taken when the infections occurred were: oral CYC (n = 11, 125 (46) mg/day), intravenous CYC (n = 10, mean dose of 1 (0.16) g/infusion), AZA (n = 8, 113 (52) mg/day), MMF (n = 4, 1 (0.7) g/day), infliximab, MTX or rituximab (n = 2 each).
Of the 53 major infectious episodes, 47 occurred during CS treatment, specifically intravenous MPS (n = 2), high-dose (>20 mg/day, n = 24) or low-dose oral CS (⩽20 mg/day, n = 21). For six episodes oral CS >20 mg/day was the only immunosuppressant being taken when the infection occurred, either immediately after WG diagnosis before the CYC introduction or during WG flares treated with CS alone.
No major infection was recorded for the three patients treated with cotrimoxazole alone.
Description and outcome of infectious episodes
The detailed characteristics of each infectious episode are given in table 2. Mean neutrophil and lymphocyte counts at the time of infection were 6497 and 964/mm3, respectively. In all, 4 patients were neutropenic (⩽1500/mm3; range 300 to 1500, median 850) and 24 were lymphopenic (⩽1000/mm3; range 0 to 1000, median 500).
Bronchopulmonary infections (n = 19, 36%) were the most frequent and required admission to intensive care units in three cases. Herpes zoster recurrences of the nine (17%) affected patients involved thoracic or thoracoabdominal metameres in all but one case (V1 facial nerve) and occurred after a median of 5 years (range 1 to 11 years) after WG diagnosis when they had a median age of 55 years (range 44 to 66 years). Two patients developed herpes zoster recurrences after WG treatment had been completed for 1–3 years. No extensive or necrotic forms were reported and only two patients received an antiviral agent (ie, oral valaciclovir). However, two patients developed major post zoster neuralgia.
Five patients developed opportunistic infections: fatal cerebral toxoplasmosis subsequent to HIV contamination by blood transfusion for massive epistaxis in 1985, oesophageal candidiasis in a patient with CS-induced diabetes, disseminated cytomegalovirus and herpes simplex infection (bone marrow, viraemia and oesophagitis) at the time of WG diagnosis with concomitant severe hypo-γ-globulinaemia (3.5 g/litre), cytomegalovirus retinitis, major herpes simplex stomatitis and keratitis (n = 1 each). One patient with Pseudomonas aeruginosa and Staphylococcus aureus pneumonia had concomitant bloodstream infection with Candida albicans.
Patients 15 and 21 experienced hepatitis B virus reactivation with grade IV cytolysis which regressed, respectively, under lamivudine and temporary AZA withdrawal or under adefovir and lamivudine without immunosuppressant reduction. However no viral flare was observed in the two other patients with active WG under immunosuppressants (including one taking lamivudine concomitant with AZA and CS introduction). No PJP or overt tuberculosis was reported.
Two infection-attributed deaths were recorded: fatal Staphylococcus aureus septicaemia and refractory WG and the above-mentioned cerebral toxoplasmosis. Six other deaths occurred without evidence of infection during the study period (global mortality rate of 7%).
Risk factors associated with the occurrence of infections
No significant differences in terms of age, sex, WG duration, WG organ involvement and other underlying diseases (diabetes, alcoholism, cancer and/or renal insufficiency) were found between patients with major infectious episodes and those without. Moreover, overall WG treatment at the end of follow-up did not differ significantly between patients who were infected and patients who were not infected: “ever use” of any drug, cumulative doses of CS and cytotoxic agents received during follow-up, as well as cumulated doses of these drugs expressed per year of follow-up were comparable for the patients who were infected and patients who were uninfected (table 3).
In contrast, patients with WG diagnosed before 1996 developed significantly more major infectious episodes than those with WG diagnosed during 1996 or thereafter (p<0.05). Pertinently, patients who were infected who were diagnosed before 1996 had received more CYC and especially more oral CYC at the moment of infection than patients who were infected who were diagnosed later (10.99 (13.8) vs 4.72 (4.5) g/year and 7.22 (12) vs 1.34 (2.97) g/year, respectively. They also received significantly more CYC during the first 3 years of WG treatment (18.73 (16.54) g/year vs 6.35 (5.11) g/year, p<0.05), especially more oral CYC (12.73 (15.95) g/year vs 1.38 (3.25) g/year, p<0.05) than patients who were infected who were diagnosed later. No significant difference between intravenous CYC doses for these two groups was observed.
Patients who developed early infections (before or equal the median 3 years of WG follow-up) had significantly higher cumulated doses of CYC and CS per year of follow-up until the infection occurred than those with late infections (p<0.05 and p<0.001, respectively) (table 4).
The doses of intravenous CYC received at the time of infection were significantly higher in patients with early infections than in those with late infections (p<0.05), while the doses of oral CYC did not differ significantly between these two groups. Patients with early infections were more frequently being treated with high-dose oral CS (defined as doses above 20 mg/day) than the others, (p<0.05). In contrast, AZA and MTX doses were comparable for the two groups (data not shown). The four patients who developed infections after withdrawal of WG treatment did not differ from the other in terms of additional factors for infection or WG treatment received.
Major infections are a major concern in the management of WG. They are responsible for consistently high morbidity and potential mortality, and represent some of the most severe and frequently pernicious effects of immunosuppressants used to induce remission, thereby minimising the therapeutic benefits in patients with life-threatening vasculitis.
However, global mortality and infection-related mortality were low in our population (respectively 7% and 1.8%) and were lower than the rates found in several multicentre studies (18% to 25% and 4.6% to 18%, respectively),7 10 12 but similar to those obtained in other single centre studies (4% to 20% and 0% to 8%, respectively).1 2 11 17 It might reflect the recruitment of our patients at a tertiary care centre where they had usually been referred to, or after diagnostic procedures, which excluded extremely severely affected patients who could not be transferred because of extremely severe manifestations.
Bacterial pneumonias, herpes zoster recurrences and opportunistic infections predominated in our cohort, with bronchopulmonary infections representing 36% of all major infections, in accordance to previous reports.2 11 The high proportion of herpes zoster recurrences (17%) also was comparable to that reported in previous studies (13% to 24%).2 11 However the percentage of opportunistic, mostly viral, infections (17%), was similar to that previously found in one of our prospective multicentre studies,7 18 and contrasted with the scarce cytomegalovirus infections reported by others.19 20 Unlike several previous reports, which emphasised the high PJP burden in patients with WG, no PJP was observed in our study, thereby confirming the efficacy of the anti-PJP prophylaxis.2–5 A similar comment can be made concerning overt tuberculosis which was not observed in our cohort; the four latent infections received full therapy.
Most infections occurred in patients diagnosed before 1996, which could reflect causes other than their longer follow-up duration. Our data underline that half of the major infections occurred within the first 3 years after WG diagnosis. Pertinently, major improvements of care were initiated in 1996: (1) reduction of immunosuppressive intensity, aiming to optimise immunosuppression by replacing with intravenous oral CYC as induction treatment and faster switch to maintenance therapy once remission had been obtained; and (2) expanded PJP prophylaxis after the identification of this specific risk in patients with WG.3 This change resulted in significantly lower total and especially oral CYC doses administered to patients diagnosed in 1996 and thereafter, compared to those diagnosed earlier.
The successive modifications of treatment protocols for CS (shorter high-dose therapy followed by more rapid tapering) and the oral-to-intravenous switch for CYC mean that all cohort participants were not treated in a homogenous manner and, therefore, represent the most important limitation of this study, along with its retrospective design, which also limits the analysis of risk factors associated with the occurrence of major infectious episodes.
However, major infections appeared closely associated to immunosuppression. Only 7.6% of all infectious episodes arose after immunosuppressants had been stopped, while 71.7% occurred during induction therapy or relapses and 39.6% within the first year of WG treatment. CYC and high-doses of CS (>20 mg/day), which are the pillars of WG induction treatment, may indeed be responsible for this early development of major infections, as no significant association has been detected between maintenance drugs and infectious complications. Other infections were delayed from the moment of WG induction therapy, reflecting the cumulative effect of the treatment-induced immunosuppression.
Unlike previous studies, we did not find any association between renal insufficiency and infections. According to a multicentre trial (1990 to 1993) focusing on 37 patients with WG with renal involvement, 15 patients died, including 5 attributed to PJP (with 1 concomitant cytomegalovirus infection).21
Our results underline the need for further immunosuppressant, and especially CYC and CS sparing, strategies, and the marked efficacy of PJP prophylaxis. The burden of severe viral infections should alert clinicians treating patients with WG to the critical importance of early diagnosis and appropriate antiviral treatment, especially for cytomegalovirus disease. Furthermore, the high frequency of bronchopulmonary infections in our cohort and previously reported studies might be lowered by prophylactic antipneumococcal and influenza vaccinations which should be evaluated in that setting, along with the future anti-herpes zoster vaccines.
The authors thank Janet Jacobson for editorial assistance.
Competing interests: None declared.
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