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* From the Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic, Rochester, MN.
Correspondence to: Bekele Afessa, MD, FCCP, 200 First St SW, Rochester, MN 55905; e-mail: afessa.bekele{at}mayo.edu
Abstract
Purpose: This study aims to describe the clinical course and prognostic factors of patients with small-vessel vasculitis admitted to a medical ICU.
Methods: We reviewed the clinical records of 38 patients with small-vessel vasculitis admitted consecutively to the ICU between January 1997 and May 2004. The APACHE (acute physiology and chronic health evaluation) III prognostic system was used to determine the severity of illness on the first ICU day; the sequential organ failure assessment (SOFA) score was used to measure organ dysfunction, and the Birmingham vasculitis activity score for Wegener granulomatosis (BVAS/WG) was used to assess vasculitis activity. Outcome measures were the 28-day mortality and ICU length of stay.
Results: Nineteen patients (50%) had Wegener granulomatosis, 16 patients (42%) had microscopic polyangiitis, 2 patients had CNS vasculitis, and 1 patient had Churg-Strauss syndrome. Reasons for ICU admission included alveolar hemorrhage in 14 patients (37%), sepsis in 5 patients (13%), seizures in 3 patients (8%), and pneumonia in 2 patients (5%). The median ICU length of stay was 4.0 days (interquartile range, 2.0 to 6.0 days). The APACHE III score was lower in survivors than nonsurvivors (p = 0.010). The predicted hospital mortality was 54% for nonsurvivors and 21% for survivors (p = 0.0038). The mean SOFA score was 11.6 (SD, 2.6) in nonsurvivors, compared to 6.9 (SD, 2.4) in survivors (p = 0.0004). Mean BVAS/WG scores were 8.6 (SD, 3.6) in nonsurvivors and 4.7 (SD, 4.6) in survivors (p = 0.0889). Twenty-six percent of the patients received invasive mechanical ventilation, and 33% underwent dialysis. The 28-day and 1-year mortality rates were 11% and 29%, respectively.
Conclusions: The mortality of patients with small-vessel vasculitis admitted to the ICU is lower than predicted, and alveolar hemorrhage is the most common reason for ICU admission.
Key Words: acute physiology and chronic health evaluation • critical care • mortality • vasculitis • Wegener granulomatosis
The systemic vasculitides are multisystem disorders with a very heterogeneous clinical presentation, course, and prognosis. The prevailing classification and nomenclature schemes are based largely on the size of the vessels that are most prominently afflicted in each syndrome.1 The small-vessel vasculitides—Wegener granulomatosis (WG), microscopic polyangiitis (MPA), and Churg-Strauss syndrome (CSS)—share many clinical features as well as the presence of anti-neutrophil cytoplasmic autoantibodies in the majority of patients with active disease. Some patients with small-vessel vasculitis have acute, life-threatening disease manifestations or complications of immunosuppressive therapy that require management in an ICU.
To predict the outcomes of adult patients admitted to ICU, several prognostic systems are currently in use, including APACHE (acute physiology and chronic health evaluation) II and III, simplified acute physiology score (SAPS) II, and mortality probability model II.2345 Patients with rheumatologic disorders admitted to the ICU are thought to have a higher mortality than predicted by APACHE II and SAPS II.6 Little is known about the clinical course and outcome prediction of critically ill patients with systemic necrotizing vasculitis or small-vessel vasculitis. To our knowledge, there is only one study78 describing the clinical course of 26 patients with a wide variety of different types of systemic necrotizing vasculitis admitted to the ICU, and the roles of APACHE II, SAPS II, and the Birmingham vasculitis activity score (BVAS) in predicting their mortality. More than 1 decade has passed since APACHE II and SAPS II were introduced. Since then, APACHE III has been developed and updated periodically.9 The present study was conducted to describe the clinical course, prognostic factors, and outcome of patients with small-vessel vasculitis admitted to the ICU, and to assess the role of the APACHE III prognostic system in predicting outcome.
Materials and Methods
In this retrospective cohort study, we reviewed the electronic and paper medical records of all adult patients with small-vessel vasculitis admitted to the medical ICU of Mayo Medical Center, Rochester, MN. The study was approved by the Institutional Review Board. Patients were identified from the APACHE III database. Patients who did not authorize their medical records to be reviewed for research were excluded. All patients admitted to the medical ICU with a diagnosis of WG, MPA, pauci-immune glomerulonephritis, CNS vasculitis, and CSS from January 1997 through May of 2004 were included. Patients with underlying rheumatologic diseases were not included in the study. In patients who had two or more ICU admissions during the study period, only the first admission was included in the study. Mayo Medical Center is a tertiary, teaching institution with two hospitals comprising approximately 1,900 inpatient beds. The medical ICU was located in one of the two hospitals and had 15 to 24 beds during the study period.
Patients with WG and CSS fulfilled both the 1990 American College of Rheumatology classification criteria and the Chapel Hill Consensus Conference definitions for the diseases.11011 The diagnosis of MPA was established according to the Chapel Hill Consensus Conference definition.1
Demographic data, reason for ICU admission, length of ICU stay, use of mechanical ventilation, and presence of multiorgan failure were recorded. The severity of critical illness was determined by the APACHE III prognostic system. The APACHE III prognostic system is used to calculate the probability of ICU and hospital death of patients admitted to the ICU.3 The calculation is based on the acute physiology score (APS), derived from 17 physiologic measurements, age, comorbidities, and ICU admission diagnosis and admission source.3 The APACHE III score is the sum of the scores given for APS, age, and comorbidities, and ranges from 0 to 299.3
We also collected data to calculate the first ICU day sequential organ failure assessment (SOFA) score.12 We defined sepsis using the American College of Chest Physicians/Society of Critical Care Medicine criteria.13 Data on microorganisms causing infection, source of sepsis, and antibiotic use were also recorded. Bloodstream infection was defined by the isolation of an organism in one or more blood cultures. Blood isolates of coagulase-negative staphylococci, Corynebacterium species, Bacillus species, Propionibacterium species, Peptostreptococcus species, Clostridium species, and unidentified Gram-positive rods were considered contaminant if a single blood culture yielded the organism or the clinician did not initiate treatment, considering it not a true infection. Use and duration of noninvasive positive pressure ventilation and invasive mechanical ventilation as well as the application and type of renal replacement therapy were noted.
The activity of small-vessel vasculitis was scored using the BVAS WG (BVAS/WG) instrument by recording vasculitis-specific disease manifestation documented in the medical records at the time of admission to the medical ICU.14 The BVAS/WG instrument scores signs and symptoms attributed to vasculitis, including general (arthralgias/arthritis, fever), cutaneous, mucous membrane, ear, nose, throat, cardiovascular, GI, pulmonary, renal, and nervous system manifestations, as well as other symptoms not covered by the nine core groups.14 Data regarding pre-ICU admission vasculitis status including organs involved, dose of glucocorticoid and immunosuppressive therapy at and prior to ICU admission, as well as treatment modalities aimed specifically at the vasculitis and initiated during ICU stay (including high-dose glucocorticoids, cytotoxic agents, and plasma exchange) were collected. Results of diagnostic tests from BAL specimens and biopsies of the kidneys, lung, nose, or skin were also recorded.
Diffuse alveolar hemorrhage was defined by evidence of the following: (1) widespread alveolar injury manifested by multilobar pulmonary infiltrate, symptoms and signs of pneumonia, and abnormal pulmonary physiology with increased alveolar to arterial oxygen gradient; (2) absence of infection compatible with the diagnosis; and (3) BAL showing progressively bloodier return from three separate subsegmental bronchi or the presence of 
20% of hemosiderin-laden macrophages.15 The primary outcome variable was 28-day mortality, defined as mortality in the hospital or within 28 days of hospital discharge. Secondary outcome variables included hospital mortality, 1-year mortality, and ICU length of stay. The end-of-life issues in the ICU, do-not-resuscitate status in the ICU, and withdrawal of life support were noted.
Continuous data were summarized as mean with SD if normally distributed, and as median with interquartile range (IQR) if skewed. Comparisons between groups were made using Student t test or Mann-Whitney U test for continuous variables and 
2 for categorical variables. The standardized mortality ratio with its 95% confidence interval was calculated by dividing the observed mortality by the predicted mortality rate; p values < 0.05 were considered significant.
Results
There were 38 patients with small-vessel vasculitis admitted to the medical ICU during the study period. The baseline characteristics of the patients and the severity of illness measures are listed in Table 1 . The APACHE III-predicted mortality rate was 25.7%. WG was the most common vasculitis diagnosis seen in 19 of the patients (50%). The diagnoses of 12 of the 38 systemic necrotizing vasculitides (32%) [8 WG and 4 microscopic polyangiitis] were established during that hospitalization. Alveolar hemorrhage was the most common reason for ICU admission (Table 2 ).
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Renal biopsy was performed in seven patients, and all were found to have a pauci-immune rapidly progressive necrotizing glomerulonephritis. Skin and nasal biopsies in two patients were consistent with necrotizing vasculitis. Lung biopsy showed pulmonary capillaritis in one patient and usual interstitial pneumonitis with alveolar hemorrhage in another patient.
Median ICU length of stay was 4 days (IQR, 2 to 6 days). The 28-day mortality rate was 11%. All four deaths occurred in the ICU. Septic shock was the cause of death in all patients. In one patient, septic shock occurred in combination with uncontrolled disease activity. The standardized mortality ratio was 0.41 (95% confidence interval, 0.11 to 1.06). There were statistically significant differences in the first ICU day APS, APACHE III score, predicted mortality rate, and SOFA score, but not BVAS score, between survivors and nonsurvivors (Table 4 ). The 1-year mortality rate was 29%; 11 patients died. The median BVAS score of the 1-year survivors was 4.0 (IQR, 0.0 to 9.5), compared to 8.0 (IQR, 3.3 to 9.0) of the nonsurvivors (p = 0.1663).
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Diffuse alveolar hemorrhage, followed by sepsis, was the most common reason for ICU admission in our study. This highlights the importance of including diffuse alveolar hemorrhage in the differential diagnosis of pulmonary infiltrates in the ICU. Vasculitis disease activity was the most common reason for ICU admission in 20 of the 26 patients (77%) reported by Cruz and colleagues,7 rapidly progressive glomerulonephritis and pulmonary infiltrates from CSS being the two most common reasons for ICU admission in that study. In our study, WG was the diagnosis of 42% of patients requiring intensive care management.
The 28-day and 1-year mortality rates in our study were 11% and 29%, respectively. The short-term mortality was lower than the widely held estimate of 25 to 50%.16 Godeau and colleagues17 reported the ICU and hospital mortality rates for patients with systemic rheumatologic diseases admitted to the ICU as 33% (59 of 181 patients) and 43% (77 of 181 patients), respectively. Similarly, in a retrospective review of 48 patients with systemic rheumatologic diseases admitted to the ICU, Kollef and Enzenauer18 found an overall mortality of 30%. Cruz and colleagues7 reported a similarly high overall mortality of 39% for their 26 patients with systemic necrotizing vasculitis admitted to the ICU, and 15% of the patients died in the ICU.
Septic shock (n = 4) was the leading cause of death in our study, and uncontrolled disease activity was a significant contributor in one patient. This is consistent with other studies19202122 that have identified infection and septic shock as the primary cause of death during remission induction therapy of anti-neutrophil cytoplasmic autoantibody-associated vasculitis. In patients with systemic rheumatologic diseases, the mortality has been reported to be particularly high if the reason for admission to the ICU was an infectious complication of immunosuppressive therapy (55%).17
It is difficult to predict the outcome for patients with vasculitis admitted to the ICU. Many prognostic systems have been developed to predict outcome in critical illness.234512 However, these prognostic systems may not perform well in predicting the mortality of specific subsets of critically ill patients that were not adequately represented in the development of the models. To our knowledge, only one study7 has addressed the role of ICU prognostic models in predicting mortality in patients with systemic necrotizing vasculitis admitted to a medical ICU. That study found that APACHE II and SAPS II scores were associated with short-term mortality and the vasculitis activity measured by BVAS with long-term outcome. SOFA scores are a useful tool in evaluating organ system failure in the ICU.12 Multiple organ system failure is associated with excessive mortality and morbidity in the ICU.2324 To date, the association of SOFA score and APACHE III severity measures with mortality have not been assessed in vasculitis patients. In the present study, we found an association of 28-day mortality with SOFA score as well as with APS and APACHE III scores and predicted mortality rates.
Vasculitis disease activity can be quantified using BVAS.8 The more disease-specific derivative BVAS/WG was subsequently developed and validated for the assessment of disease activity in the small-vessel vasculitides, and WG in particular.14 Scores obtained with both systems in patients with necrotizing small-vessel vasculitis correlate well.25 The study by Cruz et al7 found BVAS to be a poor predictor of ICU mortality, but correlated with the long-term outcome of patients with systemic necrotizing vasculitis. In our study, we did not find a statistically significant association between the BVAS/WG score and 28-day or 1-year mortality rates.
Even though our study represents the largest case series of patients with necrotizing small-vessel vasculitis admitted to the ICU, it has several limitations. Given the rarity of these diseases, the sample size is small. Furthermore, our study was conducted at a single tertiary referral center. This introduces the potential for referral bias, which is difficult to estimate. The referral bias may be affected by a selection of patients who can be transported, excluding the sickest patients. However, referral may be biased toward sicker patients who do not respond promptly to standard therapy for vasculitis. Consequently, our findings should not be generalized. Finally, the BVAS and BVAS/WG tools are designed to quantify disease activity prospectively in clinical trials. Even though frequently used retrospectively, such an application of these tools has a tendency to underestimate the disease activity.
Conclusions
Our study shows WG to be the most common vasculitis requiring ICU admission, and alveolar hemorrhage to be the most common reason for admission. In one third of the cases, the diagnosis of vasculitis was established during this acute hospitalization. We also noted nonsurvivors to have higher APS, APACHE III, and SOFA scores on ICU admission compared to survivors. Because of the small sample size, we did not find a statistically significant association between BVAS/WG score and 28-day or 1-year mortality rates. A multicenter study with larger sample size is warranted.
Footnotes
Abbreviations: APACHE = acute physiology and chronic health evaluation; APS = acute physiology score; BVAS = Birmingham vasculitis activity score; BVAS/WG = Birmingham vasculitis activity score for Wegener granulomatosis; CSS = Churg-Strauss syndrome; IQR = interquartile range; MPA = microscopic polyangiitis; SAPS = simplified acute physiology score; SOFA = sequential organ failure assessment; WG = Wegener granulomatosis
This study was supported by The Academic Empowerment and Mentorship Project for Underrepresented Minorities, Department of Medicine, Mayo Clinic College of Medicine.
The authors have no conflicts of interest to disclose.
Received for publication October 8, 2006. Accepted for publication December 6, 2006.
References
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