Characteristics and Risk Factors of Severe infection in ANCA-associated vasculitis

doi:10.21203/rs.3.rs-3100026/v1

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Characteristics and Risk Factors of Severe infection in ANCA-associated vasculitis

https://doi.org/10.21203/rs.3.rs-3100026/v1

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Background: There is a close relationship between ANCA-associated vasculitis and infections. Based on a cohort of ANCA-associated vasculitis patients from East China, this study aimed todescribe the infection characteristics and prognosis of the patients, and explore the risk factors for severe infections.

Methods: Relevant data from the cohort of ANCA-associated vasculitispatients (n=82) at the affiliated Huashan Hospital, Fudan University, collected between 2012 and 2021 was retrospectively reviewed to describe the basic characteristics and treatment response of the completely relieved vasculitis patients (n=63) and non-completely relieved AAV patients (n=19), and to compare the incidence of severe infections and prognosis between AAV patients with underlying infections (n=17) and those without infection(n=65).

Results: 65% of the infections occurred within the first three months of AAV-induced treatment. The main site of common infection was the urinary system, with Escherichia coli being the most common pathogen. The main site of severe infections was the respiratory system, and the main pathogenic bacteria included Klebsiella pneumoniae, Candida albicans, and Aspergillus. The complete remission rate of patients with underlying infections before diagnosis of AAV was lower than that of patients without underlying infections before the onset of the disease (58.82% vs 81.84%, p=0.048), and even if the dose of immunosuppressants was reduced, the incidence of severe infections in patients with underlying infections was higher than that in patients without infections (63.64% vs 32.36%, p=0.0055). The presence of underlying infections at the time of diagnosis of AAV (HR=4.569, 95% CI=1.518-14.302, p=0.007), elevated ALT at the onset of the disease (HR=3.163, 95% CI=1.060-9.371, p=0.039), and the use of cyclophosphamide (HR=4.081, 95% CI=1.246-13.279, p=0.020) were found to be the risk factors for severe infections.

Conclusions: Bacterial and fungal pneumonia are the main types of severe infection after ANCA-associated vasculitis immunosuppressive therapy. The presence of underlying infection and impaired liver and kidney function at the time of diagnosis of AAV are independent risk factors for severe infections in ANCA-associated vasculitis patients after receiving immunosuppressive therapy. Patients with underlying infection with AAV have a lower complete response rate and are still prone to severe infection after receiving reduced immunosuppressive therapy.

ANCA-associated vasculitis

immunosuppressive therapy

severe infections

Antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) is a type of vasculitis characterized by the presence of ANCA antibodies in the serum, affecting both large and small vessels in multiple systems(1). The application of immunosuppressants has improved the survival rate of AAV patients(2–5). However, the adverse reactions such as infections, cardiovascular events, and malignancies(6) have greatly impacted the prognosis of AAV patients, and infections have become the leading cause of death among AAV patients(7, 8). The reported infection rates after AAV treatment are inconsistent both domestically and abroad, and the management of AAV treatment is faced with the biggest challenge of infections after immunosuppressive therapy. Currently, there are few reports on the risk factors for severe infections in Chinese AAV patients after immunosuppressive therapy, and the optimal immunosuppressant dose and reduction scheme to reduce infection events are relatively lacking. This study is based on the AAV cohort at Fudan University Affiliated Huashan Hospital and uses traditional culturing and second-generation sequencing technology to detect the pathogens in infected patients. The study describes the infection characteristics of AAV patients receiving immunosuppressive therapy, analyzes the risk factors for severe infections, and provides relevant information for the treatment management of AAV patients.

Patients

This study is a retrospective cohort analysis that includes 189 patients newly diagnosed with ANCA-associated vasculitis (AAV) between January 1, 2012 and December 31, 2021 at Fudan University Affiliated Huashan Hospital. All patients met the criteria for AAV according to the Chapel Hill Consensus Conference nomenclature(9). Excluded were patients who were pregnant, had malignancies, blood diseases, other forms of vasculitis besides AAV, or who did not agree to participate in the study or did not sign the informed consent form. The included patients had a follow-up time of at least 6 months and received treatment with cyclophosphamide combined with glucocorticoids immunosuppressive therapy (the specific process is shown in Fig. 1). The final number of AAV patients included in the study was 82. Disease activity was measured using the Birmingham Vasculitis Activity Score (BVAS)(10–12). The epidemiology, clinical characteristics, and risk factors of concurrent infections in 82 AAV patients during treatment were described. This study was conducted in accordance with the Helsinki Declaration. The study protocol was approved by the Human Research and Ethics Committee of Huashan Hospital Affiliated to Fudan University (KY2016-394). All registered patients signed a written informed consent form.

Methods

Patients were treated with an immunosuppressive regimen throughout the observation period: patients with severe or life-threatening disease were given an additional intravenous injection of methylprednisolone 120–500 mg for 3–5 days, followed by oral 1 mg/kg/day for 1 month, then gradually reduced to 30–40 mg/day after 1 month, and then 10–20 mg/day after 3 months, continuing to maintain a dose of 4 mg/day(13, 14). At the same time, patients received 15 mg/kg intravenous cyclophosphamide monthly for 6 months, repeated at 8, 10, and 12 months, adjusted according to kidney function and age according to the CYCLOPS program(15). Patients with creatinine ≥ 500 µmol/l or life-threatening pulmonary hemorrhage received plasma exchange. In this study, 20 patients received plasma exchange. The amount of plasma exchange per exchange was 60 mg/kg, with a course of daily or every other day for 14 days, until ANCA or converted to negative. After 12 months, it was switched to sulfasalazine for the maintenance period, and at the same time, oral 4 mg of methylprednisolone was given daily or every other day as a long-term maintenance treatment for at least 24 months.

Data Collection

Clinical, biological, and immunological data were collected at the time of AAV diagnosis, during infection outbreaks, and at the final visit. The cumulative doses of CTX, GC, and AZA were calculated at the time of infection and at the end of follow-up using the method described by Stuck et al. (i.e., average daily dose multiplied by treatment days)(16). Other risk factors for infection, such as concurrent diabetes, renal impairment, the presence of underlying infection, and additional intravenous methylprednisolone, were also collected.

Definitions

Infection is defined as an observable clinical symptom, microbiological detection, and/or radiological suspicion requiring hospitalization and antibiotic treatment. The hospital must have at least one ICD-10 infection code and infection must be confirmed within 6 months of the last contact with glucocorticoids and/or immunosuppressive agents. A common infection is defined as only laboratory or imaging evidence with no symptoms or mild symptoms without intravenous antibiotic, antifungal or antiviral drugs. Severe infection is defined as intravenous antibiotics, antifungal or antiviral drugs, radiology or surgical intervention, endangering life consequences such as sepsis, shock, hypotension, acidosis, etc(17–19).

Efficacy Assessment

Complete remission is defined as no clinical disease activity, such as a BVAS of 0 and sustained for 2 months(20). Sustained remission is defined as no disease activity for at least 6 months (BVAS is 0). Recurrence is defined as any disease activity caused by active vasculitis (based on BVAS score). End-stage renal disease (ESRD) is defined as renal function not recovering for at least 12 consecutive weeks, requiring renal replacement therapy (hemodialysis, peritoneal dialysis, and/or continuous renal replacement therapy) or kidney transplant(21). Death is determined by 2 practicing physicians with at least 5 years of clinical work experience and have received standardized brain death determination training(22). The primary endpoint of this study is severe infection events. Secondary endpoint includes complete remission rate and incidence of ESRD.

Data Analysis

Continuous variables are represented by the mean ± standard deviation (x ± s) (normal distribution) or median M (P25, P75) (non-normal distribution). Differences between two groups are compared using a T-test (normal distribution) or Mann-Whitney U test (non-normal distribution), count data is represented as a percentage, and differences between two groups are compared using a chi-square test.

The Wilcoxon test for two independent samples is used to compare two independent non-normal distribution data; COX regression is used to evaluate the relationship between common risk factors and severe infection related to AAV. In single-factor analysis, P values < 0.1 are included in the multi-factor analysis, and according to the spearman correlation analysis, each factor is judged to be interrelated. Considering that baseline infection will affect initial CTX and corticosteroid dose and cumulative CTX dose, in the final multi-variable COX proportional risk model, only five variables are included, which are not related variables. Regression results are shown as hazard ratio (HR) and 95% confidence interval (CI).

The above statistical analysis was performed using Stata/MP 13.0, and a p-value of < 0.05 was considered statistically significant.

Characteristics of Infections after immunosuppressive therapy

82 patients at Huashan Hospital Affiliated to Fudan University between 2012 and 2021were enrolled, with a follow-up range of 1 to 93 months (median 17.2 months). A total of 55 patients (55%) had 143 infections. 35 patients had severe infections with a rate of 28.0%, and there were 37 secondary infections, 14 third infections, and 8 fourth infections. Two patients experienced the fifth and sixth infections, respectively. During the induction therapy period (median 3 months), 55 patients had 93 infections (65%). During the maintenance therapy period (median 24 months), 32 patients had 50 infections (35%). Lung infections (n = 38, 26.5%) were the most common type of infection, followed by urinary tract infections (n = 16, 11.2%), skin and soft tissue infections (n = 8, 5.6%), and digestive tract infections (n = 5, 3.5%). 7 patients were diagnosed with sepsis.

In this study, 65% of the infections occurred within the first three months of induction therapy, with the main infected areas including the lungs and urinary tract. The main site of common infections was the urinary system, with Escherichia coli commonly identified through midstream urine culture. The main site of severe infections was the lungs, and the pathogens were identified through imaging examinations or laboratory tests such as G test, GM test, gelation test, deep sputum culture, blood culture, bronchoalveolar lavage fluid, and second-generation sequencing of pleural fluid. The common bacterial pathogens were Klebsiella pneumoniae, while the common fungal pathogens were Aspergillus and Candida albicans (Tables 1 and 2).

Table 1

Pathogens of non-severe infections
	Pathogens (n = 26)	N(%)
Bacterium	Kreber Pneumonia	2(7.1)
	Escherichia Coli	4(14.3)
	Enterococcus faecium	3(10.7)
	Proteus mirabilis	1(3.6)
	Corynebacterium	1(3.6)
	Lactobacillus	1(3.6)
	Enterobacter cloacae	1(3.6)
	Pseudomonas putida	1(3.6)
	Klebsiella oxytoca	1(3.6)
	Staphylococcus capitis	1(3.6)
	Citrobacter	1(3.6)
	Citrobacter freundii	1(3.6)
Fungus	Candida albicans	4(14.3)
Virus	Human herpes virus	6(21.4)
Mycobacterium	Mycobacterium tuberculosis	2(7.1)

Table 2

Pathogens of severe infections
	Pathogens (n = 60)	N(%)
Bacterium	Klebsiella pneumoniae	8(13.3)
	Escherichia Coli	4(6.7)
	Staphylococcus epidermidis	1(3.3)
	Enterococcus faecium	1(3.3)
	Acinetobacter baumannii	1(3.3)
	Pseudomonas maltophilia	1(3.3)
	Proteus mirabilis	1(3.3)
	Haemophilus influenzae	1(3.3)
	Pseudomonas aeruginosa	1(3.3)
	Nocardin	1(3.3)
	Bacillus cereus	1(3.3)
Fungus	Aspergillus	14(46.7)
	Candida albicans	2(6.7)
	Mucor	2(6.7)
	Pneumocystis	1(3.3)
Virus	Epstein-Barr virus	1(3.3)
	Cytomegalovirus	5(8.3)
	Varicella-zoster virus	3(5)
Mycobacterium	Nontuberculous mycobacteria	1(3.3)

Baseline Characteristics and Prognosis of Patients in Different Treatment Response Groups of AAV

Studies abroad have found that the treatment response of AAV is related to various factors, including the type of vasculitis, accumulated dose of cyclophosphamide, involvement of ear, nose, and throat at the time of onset, residual renal function, and infection(23, 24). Due to the lack of such research in the Asian population, it is worth exploring whether infection plays an important role in treatment response in the AAV queue of this center. For this reason, the center divided the AAV queue into two groups based on treatment response, and the basic information of the study population is as follows (Table 3).

Table 3

Clinical characteristics of AAVaccording to treatment response
Variables	Total(n = 82)	CR(n = 63)	NCR(n = 19)	P value
male(n,%)	25(30.49%)	18(28.57%)	7(36.84%)	0.492
age	65(54,71)	65(53,71)	65(56,71)	0.805
BMI	22.27(19.92,24.68)	22.27(19.56,24.68)	22.13(21.13,24.97)	0.674
DM (n,%)	7(8.54%)	6(9.52%)	1(5.26%)	0.560
basic infection(n,%)	17(20.73%)	10(15.87%)	7(36.84%)	0.048
PULSE-MP(n,%)	76(92.68%)	59(93.65%)	17(89.47%)	0.540
MP-reduce (n,%)	38/79(48.1%)	31/63(49.21%)	7/16(43.75%)	0.696
MP cumulative (mg)	740.7(586.7,900.0)	754.7(586.7,909.1)	711.0(571.0,857.0)	0.729
CTX-ref (n,%)	48(58.54%)	38(60.32%)	10(52.63%)	0.551
CTX dose(g)	0.62 ± 0.20	0.63 ± 0.21	0.61 ± 0.20	0.787
CTX cumulative(g)	2.2(1.2,4.5)	2.7(1.2,5.6)	1.2(0.6,2.2)	0.002
BVAS	19(16,22)	18(16,22)	19(16,22)	0.655
RBC,10¹²	3.32(2.75,3.75)	3.44(2.94,3.84)	2.74(2.50,3.17)	0.002
WBC,10⁹	8.86(6.75,11.77)	8.80(7.00,11.12)	8.90(5.75,12.76)	0.784
PLT,10⁹	261.0 ± 104.8	282.2 ± 101.6	190.7 ± 84.4	0.000
Hb,g/L	92.0 ± 23.0	97.0 ± 20.0	75.5 ± 25.1	0.002
ALT,IU/L	15.0(11.0,20.0)	15.0(11.0,21.0)	15.0(10.0,20.0)	0.775
AST,IU/L	17.0(14.0,23.0)	17.0(14.0,23.0)	17.0(14.0,38.0)	0.563
ALB,g/L	32.3 ± 5.8	32.9 ± 5.8	30.2 ± 5.1	0.063
GLB,g/L	31.9 ± 7.9	32.0 ± 7.5	31.5 ± 9.3	0.835
BUN,mmol/L	8.93(5.70,17.6)	8.2(5.0,11.7)	27.34(8.50,35.4)	0.000
SCR,umol/L	180.5(98.0,320.0)	148.0(72.0,234.0)	370.0(290.0,666.0)	0.000
eGFR,ml/min/1.73m²	29.47(14.00,51.18)	34.72(21.09,75.40)	10.39(6.61,14.28)	0.000
UA mmol/L	365.6 ± 143.5	346.0 ± 139.2	430.5 ± 141.8	0.030
IgG,mg/ml	14.65(10.65,19.05)	15.15(10.90,18.70)	11.60(10.5,19.4)	0.588
CRP, mg/dl	32.45(4.47,93.9)	29.35(4.16,90.8)	37.8(5.42,106.0)	0.817
PCT,ng/L	0,16(0.06,0.53)	0.12(0.05,0.28)	0.65(0.24,1.04)	0.000
ESR,mm/h	60(29,120)	61(30,120)	43(21,85)	0.391
p-ANCA(n,%)	63/80(78.75%)	46/61(75.41%)	17(89.47%)	0.191
MPO	137.6 ± 112.8	132.6 ± 112.9	153.7 ± 114.3	0.486
c-ANCA(n,%)	17/80(21.25%)	13/61(21.31%)	4(21.05%)	0.981
PR3	2.0(1.0,3.2)	2.0(1.0,3.2)	2.0(1.2,3.2)	0.855
infection(n,%)	42(51.22%)	30(47.62%)	12(63.16%)	0.235
severe infection(n,%)	17/42(40.48%)	9/30(30.0%)	8/12(66.67%)	0.029
ESRD (n,%)	16(19.51%)	4(6.35%)	12(63.16%)	0.000
Continuous variables are expressed as mean (standard deviation) or median (P25-P75). BMI,Body Mass Index; DM,Diabetes Mellitus;PULSE-MP, Methylprednisolone pulse therapy; MP-reduce, Rapid glucocorticoid taper; MP cumulative, Cumulative dose of CTX until infection onset/end of observation period; CTX-ref, Standard cyclophosphamide starting dose; CTX dose, Cyclophosphamide starting dose; CTX cumulative, dose of CTX until infection onset/end of observation period;; BVAS Birmingham vasculitis activity score; RBC, red blood cell count; WBC, blood leukocytes; PLT,platelets; HB, hemoglobin; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALB, albumin; GLB, globulin; BUN, urea nitrogen; SCR, creatinine; eGFR (simplified), glomerular filtration rate; UA, uric acid; IgG, immunoglobulin G; PCT, procalcitonin; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein.MPO, peroxidase;PR3, protease 3;CTX Cyclophosphamide, CR, complete relief ,ESRD End-stage renal disease.

In the 82 AAV patient queue, there were 25 male patients, accounting for 30.5% of the total, 63 (76.8%) were in the CR (complete remission) group, and the median time from confirmed AAV to CR was 9.8 months. There were 19 (23.2%) in the NCR (non-complete remission) group. There was no difference in age and gender composition between the two groups. In the CR group, 10 (15.9%) had infections at the time of confirmed AAV, while in the NCR group, this proportion was as high as 36.8% (7/19 cases), and the difference was statistically significant (p = 0.048). The mean hemoglobin in the CR group at the time of onset was 97.0g/L, and in the NCR group, it was 75.5g/L at the time of admission, accompanied by mild to moderate anemia, and the difference was statistically significant (p = 0.002). The median eGFR of the CR group at the time of onset was 34.72 ml/min/1.73 m², while the NCR group was 10.39 ml/min/1.73 m², and the difference was statistically significant (p < 0.001). The levels of albumin, C-reactive protein, hematocrit, and IgG were not statistically significant between the two groups. The median PTH level of the CR group at the time of onset was 0.12 ng/L, while the NCR group was 0.65 ng/L, and the difference was statistically significant (p < 0.001), further indicating that the presence of infection at the time of diagnosis is unfavorable for the treatment of AAV. Patients in the CR group received a median cumulative dose of 2.7 g of cyclophosphamide during the induction remission period, while patients in the NCR group received a median cumulative dose of 1.2 g of cyclophosphamide, the difference was statistically significant (p = 0.002). It is obvious that due to pre-existing underlying infection or severe infection after immunosuppressive treatment, the center had to reduce the dose of immunosuppressive agents, which affected the treatment response.

In the CR group, 9 cases (30.0%) developed severe infections after immunosuppressive treatment, and 4 cases (6.4%) progressed to end-stage renal disease, with a median time from diagnosis to ESRD of 65.0 months. In the NCR group, 8 cases (66.7%) developed severe infections, and 12 cases (63.2%) progressed to end-stage renal disease, with a median time from diagnosis to ESRD of 3.5 months. AAV patients receiving immunosuppressive treatment in the context of complete remission were more likely to progress to ESRD than those in the non-remission group (4/63 vs. 12/19, p < 0.001). The incidence of severe infections in CR group patients receiving immunosuppressive treatment was lower than that in the NCR group (9/30 vs. 8/12, p < 0.001).

Risk factors for severe AAV infections

The rate of severe infections in our AAV cohort is lower than in foreign countries, but the remission rate is not satisfactory. On the one hand, our center adopts a low-dose immune suppression treatment for high-risk populations, which reduces the occurrence of severe infections but at the same time affects the treatment response. Therefore, we conducted a survival analysis and a multivariate COX proportional hazard regression model for severe infections after AAV immune suppression treatment.

Even if the dose of immune suppressants was reduced based on age and kidney function, the rate of severe infections was still higher than in patients without underlying infections (63.64% vs 32.36%, p = 0.0055) (Fig. 2).

In the ANCA-associated vasculitis cohort model, after adjusting for confounders such as age, hemoglobin, and decreasing C-reactive protein, the presence of underlying infection at the time of AAV diagnosis (HR = 4.596, 95% CI = 1.518–14.302, p = 0.007), liver dysfunction (ALT) (HR = 1.020, 95% CI = 1.004–1.037, p = 0.013), and low kidney function (eGFR) (HR = 0.937, 95% CI = 0.888–0.989, p = 0.019) remained as risk factors for severe AAV infections (Table 4).

Table 4

COX regression for AAV severe infection
Varible	Univariate Cox Regression		Multivariates Cox Regression
Varible	HR (95% CI)	P value	HR (95% CI)	P value
gender(male)	1.460(0.539–3.957)	0.457	-
age(years)	1.028(0.984–1.073)	0.212
BMI	1.057(0.945–1.182`)	0.334
DM (n,%)	0.553(0.073–4.177)	0.556
basic infection(n,%)	3.623(1.370–9.581)	0.009	4.569(1.518–14.302)	0.007
MP dose(mg)	0.154(0.017–1.430)	0.1
CTX-ref (n,%)	0.188(0.061–0.577)	0.003
CTX dose(g)	0.040(0.003–0.570)	0.018
CTX cumulative(g)	0.325(0.174–0.607)	0
BVAS	0.973(0.900-1.053)	0.5
Hb,g/L	0.978(0.955-1.000)	0.054	1.006(0.971–1.042)	0.734
ALT,IU/L	1.012(0.998–1.026)	0.089	1.020(1.004–1.037)	0.013
ALB,g/L	0.939(0.866–1.019)	0.132
eGFR,ml/min/1.73m²	0.947(0.911–0.984)	0.006	0.937(0.888–0.989)	0.019
PCT,ng/L	1.122(1.032–1.220)	0.007	1.041(0.950–1.142)	0.388

For a long time, there has been a suspicion of a connection between vasculitis and infection. Bacterial infections can trigger the production of various autoantibodies, including ANCA(25). Infection is a major problem in the treatment of ANCA-associated vasculitis and is also the most common cause of death, especially in patients with malnutrition or immunosuppressive therapy(26, 27). The burden and characteristics of infections related to immunosuppressive therapy for ANCA-associated vasculitis are still not consistent internationally. This study, based on a new cohort of ANCA-associated vasculitis, including all individuals who received baseline investigation and glucocorticoid plus cyclophosphamide immunosuppressive therapy and were regularly followed up, describes the incidence and characteristics of infections after immunosuppressive therapy and explores the risk factors for severe infections.

We found that the infection rate in ANCA-related vasculitis patients receiving immunotherapy in this study was 49.0%. Harper et al. retrospectively analyzed 233 newly diagnosed ANCA-related vasculitis patients between 1990 and 2000, with an infection rate of 39.9% (93/233)(28). Charlie et al. conducted a retrospective analysis of 113 confirmed WG patients from January 1984 to March 2006, with a severe infection rate of 47% (53/113)(26). The Nanjing Hospital retrospectively analyzed 248 cases of AAV diagnosed from January 1, 1998 to December 31, 2013, with a severe AAV infection rate of 41.5% (103/248)(19). However, considering the onset age of our study population was 65 years old, urinary tract infections are often related to elderly women. At the same time, the differences in infection rate are largely related to the definition of infection. Therefore, we focus on describing the incidence of severe infection after immunosuppression therapy and risk factors. The severe infection rate in our center was 20.7% (17/82), and because our research center provides prophylactic anti-infection therapy and adjusts immunosuppressive doses in a timely manner for elderly patients, those with impaired renal function, and those with low white blood cell counts, when formulating personalized treatment plans, it is not difficult to find that for AAV patients with underlying infections, the initial and cumulative doses of cyclophosphamide are lower than for those without infections. This also explains why the incidence of severe infection in our queue is lower than in other queue studies.

In this study, 65% of infections occurred in the first three months of induction therapy. The main sites of infection include the lungs and urinary tract. Among them, the main site of common infection is the urinary tract, the pathogen is Escherichia coli, and information about the pathogen can usually be obtained by mid-urine culture; the main site of severe infection is the lung, and the pathogen can be detected by imaging examination, G test, GM test, latex coagulation test, bronchial alveolar lavage or second-generation sequencing of pleural fluid. The common pathogenic fungal species are Aspergillus and Candida, and the bacteria include Klebsiella pneumoniae. According to foreign literature, studies have shown that the most common pathogens causing disease after AAV immunosuppressive therapy are bacteria, such as Streptococcus pneumoniae and Haemophilus influenzae(29, 30). Second are fungi and viruses. In our cohort, the rate of fungal and viral infections was higher than previously reported(31), this difference may be related to racial differences. AAV patients often suffer from opportunistic pathogen infections in the presence of systemic inflammation, renal injury, malnutrition, or receiving immunosuppressive therapy(32), consistent with the results of our research center.

Common risk factors for AAV infection reported abroad include age, impaired renal function, clinical classification of rapidly progressive glomerulonephritis (RPGN), lymphocyte reduction, and immunosuppressive treatment(17, 26, 33–36).However, consensus on the risk factors for AAV infection in China has not yet been reached. In the AAV cohort model, we found that pre-existing underlying infections and initial liver and kidney dysfunction were independent risk factors for severe AAV infection. Previous studies have found that initial decline in kidney function is an important risk factor for infection in AAV treatment, consistent with our results(37). In our study, we found that AAV patients receiving immunosuppressive treatment in the fully relieved group (n = 12, 12/19) were more likely to enter ESRD (4/63 v.s. 12/19, p < 0.001) compared to the non-relieved group. The incidence of severe infection in the CR group receiving immunosuppressive treatment was lower than that in the NCR group (9/30 v.s. 8/12, p < 0.001). This further suggests that preventing the occurrence of severe infections can improve the prognosis of patients.

In conclusion, this study describes the incidence and risk factors of infections after immunosuppressive treatment based on the data of 82 retrospective cohort patients. Impaired liver and kidney function at the initial stage and existing underlying infections before the onset of the disease are independent risk factors for serious infections related to AAV immunosuppressive treatment. Early diagnosis and active treatment of infections can improve the prognosis of AAV, and the application of technologies such as second-generation sequencing will increase the detection rate of pathogens. This study provides a basis for clinical doctors to develop immunosuppressive regimens for the management of AAV.

It needs to be pointed out that the study population was selected as newly diagnosed ANCA-associated vasculitis patients mainly from the Department of Nephrology, Infectious Diseases and Rheumatology in our hospital, and the selection of the population to a certain extent limits the generalizability of the study conclusions. Although there were slight differences in treatment plans among the clinical physicians in the study cohort, the potential impact of preventive anti-infection or pneumococcal vaccination on infection could not be excluded. Additionally, due to the varying lengths of follow-up time of the study population and some patients not yet entering the maintenance period, the relationship between some risk factors and infection is not significant, and further longitudinal follow-up studies are needed to clarify. Currently, follow-up studies of the AAV cohort are also underway, and it is expected to provide more robust research evidence for the future study of AAV.

ANCA Antineutrophil cytoplasmic antibody

AAV Antineutrophil cytoplasmic antibody associated vasculitis

BVAS Birmingham Vasculitis Activity Score

CTX Cyclophosphamide

AZA Azathioprine

GC Glucocorticoids

ESRD End-stage renal disease

GM Galactomannan test

RPGN Rapidly progressive glomerulonephritis

Ethics approval and consent to participate

This study was conducted in accordance with the Helsinki Declaration. The study protocol was approved by the Human Research and Ethics Committee of Huashan Hospital Affiliated to Fudan University (KY2016-394).Informed consent was obtained from all individual participants included in the study.

Consent for publication

Not applicable

Data Availability
The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Funding

Not applicable

Authors' contributions

XWL coordinated the research and drafted the manuscript. TTW,XYZ,XYM,YHW and LLcollected data. LY analyzed and interpreted data. JX reviewed and revised the manuscript. All authors read and approved the final manuscript.

Acknowledgments

We thank all the patients, families, and referring physicians who participated in this study.

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No competing interests reported.

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Characteristics and Risk Factors of Severe infection in ANCA-associated vasculitis

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Abstract

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Background

Patients And Methods

Patients

Methods

Data Collection

Definitions

Efficacy Assessment

Data Analysis

Results

Characteristics of Infections after immunosuppressive therapy

Baseline Characteristics and Prognosis of Patients in Different Treatment Response Groups of AAV

Risk factors for severe AAV infections

Discussion

Abbreviations

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References

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