Outcome of Thirty Patients with ANCA-Associated Renal Vasculitis Admitted to the Intensive Care Unit

Abstract

The natural course of as-yet-untreated ANCA-associated vasculitis (AAV) or complications of immunosuppressive treatment may result in rapid clinical deterioration with the need of admission to an intensive care unit (ICU). The aim of this retrospective study was to assess the outcome of patients with renal AAV admitted to the ICU in a single center. We reviewed the medical records of all 218 patients with AAV followed in our department between January 2001 and December 2006 and selected those admitted to the ICU. To assess the severity of critical illness, the Acute Physiology and Chronic Health Evaluation (APACHE II) and Sequential Organ Failure Assessment (SOFA) score on the first ICU day were calculated. Birmingham Vasculitis Activity Score (BVAS) was calculated to represent the total disease activity. Thirty patients with AAV (11 women, 19 men; mean age 61.5 ± 13.2 years; 20 × cANCA, 10 × pANCA positive) were included. The most common reasons for ICU admission were as follows: active vasculitis (13 patients, 43.3 %), infections (7 patients, 23.3%), and other causes (10 patients, 33.3%). The in-ICU mortality was 33.3% (10 patients). The most common cause of death was septic shock (in 5 patients). The APACHE II (33.5 vs. 23.8) and SOFA scores (11.9 vs. 6.6), but not BVAS (11.5 vs. 16.1), were statistically significantly higher in non-survivors than in survivors (p < 0.01). In conclusion, the in-ICU mortality in AAV patients may be predicted by APACHE II and SOFA scores. While active vasculitis is the most frequent reason for ICU admission, the mortality rate is highest in patients with infectious complications.

Keywords:

• systemic vasculitis
• ANCA
• intensive care
• mortality
• outcome

INTRODUCTION

Small-vessel vasculitides—Wegener's granulomatosis (WG), microscopic polyangiitis (MPA), Churg-Strauss syndrome (CSS), and renal-limited vasculitis (RLV)—are a group of immune-mediated diseases with a strong and highly specific association with anti-neutrophil cytoplasmic autoantibodies (ANCA). The diseases share many clinical and histological features and are therefore all ranked among ANCA-associated vasculitides (AAV).[1]

The course of AAV is very heterogeneous, but in severe cases, the vasculitides can result in rapid clinical deterioration with acute, life-threatening disease manifestations that require immediate admission to an intensive care unit (ICU). In other patients, the reason for ICU admission might be a severe complication of immunosuppressive therapy.

The prediction of patient outcome is generally important in clinical medicine, and even more so in the ICU. Several methods of clinical prediction and measurement of disease severity in critically ill patients have been developed, such as Acute Physiology and Chronic Health Evaluation (APACHE) II and III, simplified acute physiology score (SAPS) II, mortality probability model II, and Sequential Organ Failure Assessment (SOFA) score.[2–5]

Patients with underlying rheumatologic diseases are thought to have a higher mortality than predicted by APACHE II and SAPS II.[6] However, a lower mortality of patients with small-vessel vasculitis admitted to the ICU than predicted by APACHE III has been demonstrated in a recent study.[7] By and large, there are few studies that describe the prognosis and outcome of patients with small-vessel vasculitides in the ICU. The aim of this retrospective cohort study was to assess the outcome of patients with AAV admitted to the ICU in a single center, including the role of APACHE II prognostic system, SOFA score, and BVAS (Birmingham Vasculitis Activity Score).

PATIENTS AND METHODS

Patients

In this retrospective study, we reviewed the paper and electronic medical records of all 218 patients with ANCA-associated renal vasculitis (WG, MPA, or CSS) regularly followed in our department between January 2001 and December 2006 (106 of them newly diagnosed in this period). All patients admitted to the intensive care unit (ICU) were included in the study. In patients with more than one ICU admission during the study period, only the first admission was registered.

Patients with WG and MPA fulfilled the Chapel Hill Consensus Conference definitions for the diseases.[8] Patients with WG also met the American College of Rheumatology criteria.[9],[10]

The following data were recorded: demographic data, duration of the disease before ICU admission, previous immunosuppressive treatment, reason for ICU admission, length of ICU stay, use of mechanical ventilation, in-ICU mortality, three-month mortality, and mortality at the end of follow-up.

METHODS

Reasons for ICU admission were classified as follows:

• active vasculitis;

• infection, either microbiologically documented or clinically suspected; and

• all other causes not attributable to active vasculitis or infection (e.g., cardiovascular disease complications).

To assess the severity of critical illness, the APACHE II score and SOFA score on the first ICU day were calculated.[2],[5] The APACHE II score includes the Acute Physiology Score (APS), which is derived from 12 variables (Glasgow coma scale, body temperature, blood pressure, heart rate, respiratory rate, ventilation, serum natrium levels, serum potassium levels, hematocrit, white blood cell count, serum HCO3 levels, and arterial pH) recorded within the first 24 hours of the ICU stay, with the most severe result used. The APACHE II score also assesses age and previous severe chronic diseases—cardiac, respiratory, renal, hepatic, and immunodeficiency. To calculate the SOFA score, the function of six major organ systems (cardiovascular, respiratory, renal, hepatic, CNS, and coagulation) is evaluated.

BVAS (Birmingham Vasculitis Activity Score) is a score representing the total disease activity in AAV patients. It scores signs and symptoms attributable to vasculitis, divided into ten basic subgroups (general, cutaneous, mucous membranes/eyes, ENT, chest, cardiovascular, abdominal, renal, nervous system, and other). In this study, BVAS 2003 modification[11] was used, and the score was calculated at diagnosis and at the time of ICU admission.

Statistical Analysis

Continuous variables are presented as mean ± standard deviation if normally distributed and as median with range if skewed. Comparisons between survivors and non-survivors were made using Student t test or Mann-Whitney U test for continuous variables and χ² test for qualitative data. The standardized mortality ratio was calculated by dividing the observed mortality by the predicted mortality rate. p values < 0.05 were considered significant for all analyses.

RESULTS

Thirty patients with AAV (11 women and 19 men, mean age 61.5 ± 13.2 years) were admitted to the ICU during the study period. The characteristics of the patients and the severity of illness measures are summarized in Table 1. All of the patients were at least once in the history of their disease ANCA positive (20 × antiPR3 positive, 10 × pANCA positive). In 12 patients, the diagnosis of AAV was newly established in the ICU. The mean time of the duration of vasculitis before ICU admission in the remaining 18 patients was 27.1 ± 32.6 months. Renal involvement (defined as serum creatinine ≥ 120 μmol/L) was present in all patients. Standard combined immunosuppressive treatment (corticosteroids and oral/pulse cyclophosphamide[12]) was administered in all patients.

Table 1 Characteristics of 30 patients with AAV admitted to the ICU*

Characteristics	Data
Age (years)	61.5 ± 13.2
Male gender	19 (63.3%)
Type of vasculitis
WG	20 (66.7%)
MPA	10 (33.3%)
APACHE II score^†	27.0 ± 10.4
SOFA^†	8.4 ± 4.3
BVASdg^†	22.3 ± 6.8
BVASICU^†	14.5 ± 11.4
Length of ICU stay (days)	6 (1 to 38)
Duration of vasculitis before ICU (months)	2 (0 to 102)
Admitted from
Another hospital department	26 (86.7%)
Home	4 (13.3%)

*Data are presented as mean ± SD, number (%), or median (range).

^†Scores calculated retrospectively, using data collected during the first 24 hours after admission to the ICU (APACHE II, SOFA, BVAS_ICU) and at the time of diagnosis of vasculitis (BVASdg).

Abbreviations: APACHE = acute physiology and chronic health evaluation, SOFA = sequential organ failure assessment, BVAS = Birmingham vasculitis activity score.

The most common reason for ICU admission (see Table 2) was active vasculitis (13 patients, 43.3%), with pulmo-renal syndrome, including alveolar hemorrhage and acute renal insufficiency, observed in 11 patients (37%). In one patient, the reason for ICU admission was acute respiratory insufficiency due to subglottic stenosis. One patient was admitted because of multi-organ failure caused by active vasculitis. There were 10 newly diagnosed patients and 3 patients with a relapse of the disease. Four of these patients received mechanical ventilation. Renal replacement therapy was necessary in four patients.

Table 2 Reasons for admission to the ICU of 30 patients with AAV

Reasons for ICU Admissions	Number (%)
Active vasculitis	13 (43.3)
Pulmo-renal syndrome	11 (36.7)
Subglottic stenosis	1 (3.3)
Multi-organ dysfunction	1 (3.3)
Infectious complications	7 (23.3)
Pneumonia	5 (16.7)
Catheter-related	1 (3.3)
Sepsis (Staphylococcus sp.)	1 (3.3)
Other reasons	10 (33.3)
Atrial fibrillation	3 (10)
Acute myocardial infarction	2 (6.7)
Pulmonary embolism	2 (6.7)
Hemorrhagic stroke	1 (3.3)
Acute left ventricular failure	1 (3.3)
Hypertensive crisis	1 (3.3)

Infectious complications were the reason for ICU admission in seven (23.3%) patients; the most common cause was bilateral pneumonia with respiratory insufficiency (in five patients, i.e., Pneumocystis carinii 2 ×; Aspergilus fumigatus 1 ×; Candida albicans 1 ×, unknown infectious agent 1 ×). One patient was admitted because of catheter-related sepsis (Enterococcus faecalis) and CMV infection. Sepsis (multi-resistant Staphylococcus epidermidis) was also observed in the last patient.

Ten patients (33.3%) were admitted for other reasons, mainly for cardiovascular diseases and their complications (see Table 2).

Median length of ICU stay in our study was six days (range 1–38). The in-ICU mortality rate was 33.3% (10 patients). The calculated standardized mortality ratio was 0.6. Septic shock was the cause of death in five patients. One patient died of sepsis caused by Staphylococcus epidermidis. In four patients, bilateral pneumonia (Pneumocystis carinii 2 ×; Aspergilus fumigatus 1 ×; infectious agent not known 1×) resulted in septic shock and subsequent death. Two patients died of active vasculitis despite immunosuppressive treatment and plasma exchange therapy, the causes of death being continuing alveolar hemorrhage in one patient and multi-organ failure in the other. In the remaining three patients who died in the ICU, the causes of death were cardiac failure, cardiogenic shock following acute myocardial infarction, and hemorrhagic stroke.

The three-month mortality rate was 46.7%. Eleven patients (36.7%) were alive at the end of follow-up (the mean time of follow-up was 24.6 ± 30.7 months).

Statistical analysis of the APACHE II, SOFA, and BVAS is summarized in Table 3. The APACHE II and SOFA scores but not BVAS (neither BVAS at diagnosis nor BVAS at ICU admission) were statistically significantly higher in non-survivors than in survivors (p < 0.01 for in-ICU mortality and three-month mortality). Interestingly, the SOFA score calculated for the first day of ICU stay (but not the APACHE II or BVAS) also significantly differed between the survivors and non-survivors at the end of follow-up.

Table 3 Differences in APACHE II, SOFA, and BVAS (mean ± SD) determined retrospectively at admission according to early (in-ICU), three-month, and end of follow-up survival

Score	In-ICU			Three months			End of follow-up
	Survivors (n = 20)	Non-survivors (n = 10)	p value	Survivors (n = 16)	Non-survivors (n = 14)	p value	Survivors (n = 11)	Non-survivors (n = 19)	p value
APACHE II	23.8 ± 10.0	33.5 ± 8.5	0.01	22.6 ± 8.9	32.1 ± 10.0	0.01	22.9 ± 10.1	29.4 ± 10.2	n.s.
SOFA	6.6 ± 3.6	11.9 ± 3.3	0.0005	6.0 ± 2.9	11.1 ± 4.1	0.0005	6.3 ± 3.3	9.6 ± 4.4	0.04
BVASdg	23.4 ± 7.6	20.1 ± 4.1	n.s.	22.1 ± 6.5	22.5 ± 7.3	n.s.	23.9 ± 6.6	21.3 ± 6.9	n.s.
BVASICU	16.1 ± 12.2	11.5 ± 9.5	n.s.	13.9 ± 10.8	15.2 ± 12.5	n.s.	14.2 ± 11.9	14.7 ± 11.5	n.s.

*Calculated retrospectively, using data collected during the first 24 hours after admission to the ICU (APACHE II, SOFA, BVAS ICU) and at the time of diagnosis of vasculitis (BVAS dg).

Abbreviations: n.s. = non-significant, APACHE = acute physiology and chronic health evaluation, SOFA = sequential organ failure assessment, BVAS = Birmingham vasculitis activity score.

DISCUSSION

ANCA-associated vasculitides represent one of the challenges in intensive care units. In patients with AAV, critical illness may be the initial presentation of the vasculitis, the result of progressive primary or recurrent/refractory disease, or the result of complications of immunosuppressive treatment. To our knowledge, there are only two previous studies[7],[13] describing the outcome of patients with vasculitis admitted to the ICU in detail and assessing the role of prognostic systems. In our study, all patients were ANCA-positive. Moreover, the patients were recruited within a relatively short period, and the therapeutic approach was therefore uniform in all patients.

Similar to previous studies,[7],[13] the most common reason for ICU admission in our study was active vasculitis (43.3%), with pulmo-renal syndrome including alveolar hemorrhage observed in most patients (36.7%). As the diagnosis was newly established in ICU in 12 patients (40%), AAV should always be considered in the differential diagnosis of patients admitted to the ICU due to severe pulmonary and/or renal manifestations of yet unknown origin.

The mortality rate of patients with systemic rheumatic diseases admitted to the ICU has been estimated at 25–50%.[14] In recent retrospective studies, the reported mortality rates were usually lower—23% for patients with rheumatic diseases[15]; 15% and 11%, respectively, for patients with vasculitis.[7],[13] In our study, the overall in-ICU mortality rate was slightly higher (33%) than in the previously mentioned studies.[7],[13] However, the predicted mortality (based on APACHE II score) in our group of patients was higher than that reported by Cruz et al.[13] for both non-survivors (71% vs. 51%) and survivors (40% vs. 22%). As Khan et al.[7] used APACHE III score, direct comparisons cannot be made. Nevertheless, the predicted mortality in their study was also lower than in our study (71% vs. 58.5% for non-survivors; 40% vs. 21.8% for survivors).

One of the reasons for the higher mortality observed in our group of patients might be the presence of renal failure. Acute renal failure is a known independent risk factor for death in patients admitted to the ICU.[16] In patients with AAV, renal insufficiency is also connected with poor prognosis.[17],[18] Because our ICU forms an integral part of a nephrology unit, where most of our patients were recruited from, renal insufficiency was present in all our patients, without exception. Acute renal failure or insufficiency was registered in 13 patients, 11 of whom required renal replacement therapy. Chronic renal insufficiency or failure (chronic kidney disease stages 2–5, according to K/DOQI[19]) was present in 17 patients; renal replacement therapy was needed in 5 patients.

On the other hand, as most of the patients (86.7%) were admitted to the ICU from another hospital department, it remains questionable whether some of the patients were not referred too late, with multi-organ failure already present. The mortality rate was extremely high, especially in the subgroup of patients admitted for infectious complications (5 out of 7 patients died, i.e., 71%), even though interpretation of the data is difficult due to the small number of patients. Nevertheless, infection was the most common cause of death in previous retrospective studies.[7].[13] Moreover, infection has been identified as the primary cause of death in patients with AAV in general,[20],[21] and admission to the ICU for an infectious complication was also connected with high mortality in patients with rheumatic diseases.[22] In our opinion, close monitoring of the AAV patients with leukopenia and/or already apparent infection is necessary, as early admission to the ICU might (hypothetically) improve the prognosis of the patients. In addition, antibiotic treatment should also be started early.

As for the role of prognostic systems (APACHE II, SOFA) in predicting the outcome of patients with AAV admitted to the ICU, our results confirm the findings of previous studies.[7],[13] Both APACHE II and SOFA scores were significantly higher in non-survivors than in survivors (for both in-ICU and three-month mortality). The first-ICU-day SOFA score was even associated with the mortality observed at the end of follow-up in our study, which highlights the importance of the severity of organ failure for the long-term prognosis.

Similarly to previous studies,[7],[13] we did not find any correlation between vasculitis disease activity (assessed by BVAS) on the first ICU day and the short-term mortality of our patients. In accordance with Khan et al.,[7] but unlike Cruz et al.,[13] the BVAS (neither BVAS on the first ICU day nor BVAS at diagnosis) was not associated with long-term prognosis in our study. It is known, however, that BVAS was designed to be assessed prospectively, and the retrospective analysis might have underestimated the score. Moreover, the group of the AAV patients admitted to the ICU is a highly selected one that has to be considered in the analysis. Nevertheless, the fact that active vasculitis was rarely the cause of death in our patients might contribute to the lack of correlation between the BVAS and mortality.

We are aware of several possible limitations of our study, as our study bears the risk of all retrospective single-center analyses. The retrospective analysis of the data might have certainly influenced the results. Furthermore, although our department serves as a referral center, the number of patients in our study is relatively small, due to the low incidence and prevalence of the disease in general. The fact that our department is a referral center for patients with vasculitis introduces the problem of referral bias, and the results may therefore be affected by a selection of patients. Given the relatively high mortality of our patients, we presume that sicker patients or those that do not respond adequately to standard therapy in particular are referred to our center, although some of the patients with the most severe disease might be excluded as they cannot be transported.

CONCLUSION

In conclusion, our study assessed the outcome and prognosis of patients with AAV admitted to the ICU in a single center. Despite modern therapeutic possibilities, the in-ICU mortality in our study remained as high as 33%. While active vasculitis was the most frequent reason for ICU admission, the mortality rate was highest in patients with infectious complications. This places an emphasis on the development and use of novel, more selective, less toxic treatment modalities. APACHE II and SOFA scores predicted the in-ICU mortality in our group of critically ill patients with AAV. In this study, no correlation between the BVAS and the prognosis of AAV patients was noted.

DECLARATION OF INTEREST

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

ACKNOWLEDGMENT

This article was supported by grant number MSM0021620807 awarded by the Ministry of Education, Czech Republic.