Impairment of lung function, health status and functional capacity in patients with ANCA-associated vasculitis

C. Newall1, S. Schinke, C. O. Savage, S. Hill and L. Harper

Division of Immunity and Infection and 1 Division of Medical Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.

Correspondence to: L. Harper, Division of Immunity and Infection, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. E-mail: L.Harper{at}bham.ac.uk


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Objective. To determine the effects of lung involvement on respiratory function in patients with ANCA-associated vasculitis and the relation to impaired health status.

Methods. Thirty patients with ANCA-associated vasculitis in remission (15 with lung involvement at diagnosis as determined by an abnormal chest X-ray) were examined. We measured lung function, skeletal muscle strength [quadriceps force (QF), respiratory muscle strength (Pimax)], exercise capacity (VO2 peak) using treadmill exercise tests, and health status using the Short Form 36 and St George's respiratory questionnaires.

Results. Exercise capacity was reduced compared with predicted values (58.2%, range 23–123%) and 18 patients showed functional aerobic impairment. Respiratory muscle function was reduced (72.1% predicted, range 20–108%) and was not related to lung involvement or steroid usage. Transfer factor correlated significantly with exercise capacity, suggesting inadequate delivery of oxygen to muscles. Nine patients had reduced transfer factor (seven with lung involvement). Patients with lung involvement had impaired gas transfer compared with those without lung involvement (96.9 ± 6 vs 113.3 ± 4.7% predicted, P = 0.04). However, there were significant abnormalities in other lung function parameters not related to previous lung involvement (eight patients had reduced forced expiratory volume in 1 s, and five patients had reduced residual volume). Twelve patients (five with previous lung involvement) had obstructive airways disease. Physical health status was impaired to a greater degree than mental health status across the whole group and was not related to lung involvement or original disease severity, but correlated with transfer factor.

Conclusion. Patients with ANCA-associated disease may have significant lung function impairment irrespective of lung involvement at the time of diagnosis. Patients showed reduced respiratory muscle strength, health status and exercise capacity, which correlated with reduced transfer factor.

KEY WORDS: ANCA-associated vasculitis, Lung, Exercise, Quality of life


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Wegener's granulomatosis and microscopic polyangiitis and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides are multisystem diseases that frequently involve the lungs [1]. Early lung involvement, particularly pulmonary haemorrhage [2], is a poor prognostic factor. However, little is known regarding the long-term effects on lung function in patients presenting with lung involvement. It has been suggested that the most common abnormality in those with active disease is obstruction to airflow [3,4] but pulmonary fibrosis [5] and reduced diffusing capacity [6] may also occur. Serial evaluations in one study suggested improvements in lung function with treatment but a persistent reduction in diffusing capacity was common [6]. These small studies were performed on patients with Wegener's granulomatosis, in which the most common abnormality was granulomatous inflammation. Microscopic polyangiitis is manifest pathologically as capillaritis in the lungs; however, only case reports have investigated long-term outcome in these patients [5].

Patients with ANCA-associated vasculitis remain substantially physically impaired following treatment. In a recent study of patients with ANCA-associated vasculitis, perceived health status using the Short Form 36 (SF-36) remained significantly lower than in the normal population, particularly the factors measuring physical health, despite disease remission [7]. It was unclear from the study whether this was due to poor rehabilitation, vasculitic damage or side-effects from therapy. Corticosteroids, along with cytotoxic agents, are the mainstays of treatment in vasculitis [8]. Common side-effects of these drugs include proximal myopathy; indeed in patients with chronic obstructive pulmonary disease (COPD) corticosteroids have been associated with myopathy affecting respiratory and peripheral muscles, resulting in reduced exercise tolerance [9]. No studies investigating the association of pulmonary function or aerobic impairment with exercise tolerance have been performed in patients with ANCA-associated vasculitis.

We aimed to undertake a pilot study to assess the long-term impact on lung function and the relationship to exercise capacity and health status in patients with ANCA-associated vasculitis who presented with pulmonary involvement compared with those who had no clinical evidence of lung involvement at diagnosis. This study was approved by the local ethics committee and performed in accordance with the Declaration of Helsinki. Informed consent was obtained from patients prior to the study.


    Methods
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Subjects
Thirty patients (22 male; median age 62.5 yr, range 33–77) with biopsy-proven systemic vasculitis (14 patients with Wegener's granulomatosis, 16 patients with microscopic polyangiitis) were investigated; all had evidence of multiple organ involvement at diagnosis (Table 1). Fifteen patients had lung involvement manifest as the presence of infiltrating or cavitating lesions on chest X-ray; the remaining 15 patients had a normal chest X-ray at presentation. The groups of patients with and without chest X-ray changes were categorized as with and without lung involvement respectively. A normal chest X-ray does not exclude disease involvement within the lung; however, we used this as a simple way to categorize patients in this retrospective study. Patients with dual-positive ANCA and anti-GBM antibodies were excluded from the study. Patients were assessed for disease severity at the time of diagnosis using the Birmingham Vasculitis Activity Score (BVAS), a validated index that comprises a weighted item list, which assesses activity attributable to active vasculitis. All patients were in remission at the time of study with no evidence of active disease (BVAS = 0). The interval from the time of diagnosis ranged from 6 to 115 months. At the time of the study, 29 patients were receiving steroids [median dose 7.5 mg (range 5–12.5 mg) over the period of follow-up]. To ensure our findings were stable, 20 of the patients had investigations repeated after 6 months; no difference was found in the measured parameters.


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TABLE 1. Clinical characteristics of the patients in the study

 
Assessments
Spirometric measurements were performed using a wedge bellows spirometer (Model S; Vitalograph, UK) and included assessment of vital capacity (VC), forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1). Functional residual capacity was estimated via the steady-state helium dilution method (Benchmark; Morgan Medical, Gillingham, UK) from which residual volume and total lung capacity were calculated. All tests were performed according to national guidelines [10] and the results compared with standard reference values [11]. Transfer factor (TLCO) was measured using the single-breath method (Benchmark; Morgan Medical) according to the ARTP/BTS guidelines [10]. Measurement of diffusing capacity (Dm) and pulmonary capillary blood volume (Vc) was performed according to a previously published method [12]. The values of TLCO at standard and high oxygen concentrations were used to determine Dm and Vc by solving the Roughton and Forster equation [13]. These measurements were compared with published reference values [11]. All results were corrected for haemoglobin concentration.

Respiratory muscle strength was measured using a handheld mouth pressure meter as previously described. The quadriceps muscle was used to measure peripheral muscle strength. Quadriceps force (QF) was assessed during a maximal isometric knee extension manoeuvre (Cybex Norm; Cybex International, Ronkonkoma, NY, USA). Each patient performed five manoeuvres with a rest period of 30 s between each successive repetition. The peak torque was recorded in Newton metres (Nm) from three technically acceptable and reproducible manoeuvres (within 5%) and results were compared with predicted reference values [14].

Exercise testing was performed on a cycle ergometer (Lode; Morgan Medical) using a ramped protocol increasing at a rate of 5, 10, 15 or 20 watts/min depending on the patient's ability. During the test, breath-by-breath measurements were made of inspired ventilation (Vi), expired ventilation (Ve), oxygen uptake (VO2) and carbon dioxide output (VCO2) (Pulmolab, 670; Morgan Medical). Heart rate and oxygen saturation were recorded every minute via an ear probe connected to a pulse oximeter (Ohmeda Biox 3700; Ohmeda, UK) respectively. Patients were required to rate symptoms of breathlessness and leg fatigue at rest, at 1-min intervals throughout the test and at peak exercise using a modified Borg scale [15]. The peak oxygen uptake was recorded in l/min and compared with predicted normal values [16].

The aerobic impairment index (AII) [17], a quantitative measure of functional aerobic impairment, was calculated using the following formula: AII = (expected peak oxygen consumption – measured peak oxygen consumption)/expected peak oxygen consumption x 100, where both peak and expected oxygen consumption were expressed as ml/min/kg. Interpretation of AII scores was as follows: <26%, no impairment; 27–40%, mild impairment; 41–54%, moderate impairment; 55–68%, marked impairment; >68%, extreme impairment.

Health status was assessed using The St George's Respiratory Questionnaire (SGRQ) and the Short Form 36 (SF-36). The SGRQ is divided into three domains: symptoms, activity and impacts, from which a summary score (total) is derived. All domains are scored using a 0–100 scale, higher scores indicating greater impairment [18]. The SF-36 assesses general health concepts and is divided into eight domains. The final scores are presented as two overall scores—the Physical Component Summary Score (PCS) and the Mental Component Summary Score (MCS)—and range from 0 to 100, lower scores indicating greater impairment [19].

Statistical analysis
The data were analysed using a computerized statistical package (Intercooled Stata version 7.0; Timberlake Consultants, London, UK). The frequency distribution of the majority of the measured parameters was normal and hence the descriptive statistics are displayed as mean ± S.D. with the range given in parentheses.

Correlations between paired variables were performed using Pearson's product moment correlation. To identify independent factors predicting exercise capacity, lung function and skeletal muscle strength parameters showing significant bivariate correlations with exercise capacity were entered as independent variables into a multiple regression analysis, with peak work rate and peak oxygen uptake as dependent variables. Similarly, to identify predictors of health status, measurements of muscle strength, exercise capacity and lung function were entered as independent variables into a multiple regression analysis and the components of the SGRQ and SF-36 were examined in turn as dependent variables.

Comparisons between exercise parameters, measurements of skeletal muscle strength, and health status for patients with and without vasculitic lung involvement were performed using an unpaired t-test (with correction for multiple comparisons performed using Bonferroni correction).

A P value of <0.05 was taken as significant for all analyses.


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Lung function parameters
Evaluation of the study population revealed that nine patients (30%, seven of whom had lung involvement) had a reduced transfer factor (mean value 5.59 ml/min/kPa/l, range 4.23–7.70; 69.8% predicted). Patients who had previous lung involvement had significantly lower measurements of transfer factor (96.9 ± 6.0 vs 113.3 ± 4.7% predicted, P = 0.04) and lower measurements of pulmonary capillary blood volume (67 vs 98% predicted, P = 0.02), which may suggest loss of the alveolar capillary bed when compared with patients with no lung involvement (Table 2). Eight patients (26%, only three of whom had lung involvement) had a reduction in FEV1 (mean value 1.88 l, range 0.90–2.89 l; 62.6% predicted) and five patients (17%, two with lung involvement) had a reduction in residual volume (mean value 1.64 l, range 1.22–1.97 l; 71.4% predicted). There were no other differences in lung function parameters between the two groups of patients, nor were there any significant differences between lung function parameters in patients with Wegener's granulomatosis and patients with microscopic polyangiitis, although there was a tendency for pulmonary capillary blood volume to be lower in the former group (68.3 ± 19.0 and 92.7 ± 44.2% predicted respectively, P = 0.08). Neither the BVAS score nor ANCA titre at diagnosis related to any of the measured lung function parameters.


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TABLE 2. Demographic characteristics, lung function and skeletal muscle strength measurements

 
KCO is affected by age and, as expected, there was a negative correlation between age and KCO. The median age of the patients was 68 yr, we therefore did a subanalysis comparing those with and without lung involvement over the age of 68 yr. In those over 68 yr, KCO remained below predicted in those with lung involvement (KCO predicted 87.4 ± 17%) compared with those with no lung involvement (KCO predicted 107.8 ± 18%) (P = 0.004). The predicted Dm and Vc remained reduced in those with lung involvement compared with those without, irrespective of age, but due to small numbers did not achieve statistical significance (results not shown).

In total there were 12 patients with evidence of obstructive airways disease (FEV1/FVC ratio <70%). This was not related to either disease type (seven patients with MPA, five with Wegener's granulomatosis) or to whether there was lung involvement at diagnosis (seven patients with no lung involvement, five patients with lung involvement). There was a tendency for patients with obstructive airways disease to have a greater smoking history (22.8 ± 26.2 and 11.2 ± 15.5 pack yr for patients with and without obstructive airways disease respectively, P = 0.07), but this did not achieve statistical significance. There was no evidence of a significant restrictive ventilatory defect in any of the patients studied. It is unlikely that smoking history can explain all our findings. Smoking history did not differ between patients with and without lung involvement (18.7 ± 20.2 and 13.8 ± 22.7 pack yr respectively, P = 0.47) and there were no correlations between smoking history and any of the parameters measured. Furthermore, four out of the 12 patients with obstructive airways disease had never smoked.

Exercise performance
Twenty-eight patients were able to complete a satisfactory incremental cycle ergometer test (Table 3). The remaining two patients were unable to complete the test due to arthritis. Exercise capacity was significantly reduced compared with predicted values (mean peak work rate 76.3 watts, range 20–180 watts; mean 58.4% predicted, range 23–123%) with significant reductions in peak oxygen consumption, VO2 (mean 1.16 l/min, range 0.60–2.16 l/min; mean 68.0% predicted, range 32.0–107.0%), for the whole group. The majority of patients (n = 18) cited leg fatigue rather than dyspnoea as the reason for terminating the test. In patients with vasculitic lung involvement there was a trend towards lower peak oxygen consumption and peak work rate compared with patients without vasculitic lung involvement (Table 3), although this did not achieve statistical significance (VO2 63.8 ± 20.5 vs 71.9 ± 17.2% predicted and peak work rate 51.8 ± 24.6 vs 65.0 ± 26.4% predicted).


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TABLE 3. Results obtained during the maximal incremental cycle ergometer test

 
An AII above 26% has previously been determined to be abnormal and functionally important [17]. Eighteen patients showed evidence of impairment (nine patients with mild impairment, four patients with moderate impairment, three with marked impairment and the remaining two with severe functional aerobic impairment). Patients with Wegener's granulomatosis were more impaired than those with microscopic polyangiitis (AII 25.2 ± 12.0 and 39.3 ± 23.6% respectively, P = 0.06). This was reflected by lower measurements of peak oxygen uptake (60.8 ± 23.6 and 74.5 ± 12.0% predicted respectively, P = 0.06) and peak work rate (48.1 ± 28.9 and 68.0 ± 20.7% predicted, P = 0.05) in patients with Wegener's granulomatosis. Lung function indices, except residual volume, correlated with exercise capacity measured using VO2 peak or peak work rate; the strongest correlation was between transfer factor and VO2 peak (r = 0.736, P<0.01), suggesting that inadequate oxygen delivery to the exercising muscle may be limiting exercise performance. Pulmonary capillary blood volume was also significantly correlated with both VO2 peak (r = 0.525; P<0.01) and peak work rate (r = 0.437, P<0.01).

Skeletal muscle function
Both inspiratory (mean Pimax 70.8 cmH2O, range 14–121 cmH2O; mean 72.1% predicted) and expiratory muscle strength (Pemax; mean 103.2 cmH2O, range 50–164 cmH2O; mean 62.1% predicted) were reduced in the whole group, the reduction being greatest in those with reduced quadriceps strength (Pimax 67.6 ± 24.9% predicted vs 84.1 ± 14.1% predicted in patients with reduced and normal QF). However, there was no correlation between cumulative steroid dose or median daily dose and respiratory or peripheral muscle strength, and the reduction in strength was not related to disease type or presence or absence of lung involvement. Exercise capacity correlated with respiratory muscle strength and quadriceps force, suggesting that muscle weakness may also contribute to reduced exercise capacity.

Health status scores
Health status scores were reduced across the whole group (SGRQ total score 30.7, range 0–71.7) and reflected impaired physical health (SF-36 PCS 37.7, range 16.5–57.9) to a greater degree than mental health (SF-36 MCS 49.4, range 26.4–62.2). Measurements of physical health status correlated with peak oxygen uptake measured during the exercise test (SF-36 PCS, r = 0.432, P = 0.03; SGRQ activity domain, r = –0.548, P = 0.003). There were no differences in health status between patients with or without lung involvement at diagnosis, and initial disease severity (BVAS score) was not related to current health status.

Independent predictors of performance
In a multiple regression analysis, transfer factor remained an independent predictor of exercise capacity, and explained 52% of the variability in both peak oxygen uptake and peak work rate (P<0.001). The main predictors of health status were peak work rate and predicted peak VO2. These explained 39% of the variability in the SGRQ total score (P<0.001) and 47% of the variability in the SGRQ activity score (P<0.0001).

There was a large difference in the length of disease follow-up across the patients. We could find no correlation between any of the parameters measured and time from diagnosis.


    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The results obtained in this pilot study have demonstrated that patients with ANCA-associated vasculitis may display significant impairment of lung function despite the absence of previous active lung disease on initial screening chest X-ray. Furthermore, the severity of disease at diagnosis (BVAS score) and the presence or absence of lung involvement was unrelated to the extent of chronic physiological impairment. Measurement of transfer factor was found to be the most important predictor of exercise capacity in these patients, which in turn was central to the reduction in health status observed. The presence of clinical vasculitic lung involvement could not wholly account for the differences in exercise tolerance between the patients studied and was not a prerequisite for physiological impairment of lung function. Our study confirmed the findings of others; the commonest abnormality detected was obstruction of airflow [3,4] and reduced diffusing capacity [6]. Previous vasculitic lung disease appears to cause persistent scarring and loss of the alveolar capillary bed as patients with previous lung involvement had persistent reduced transfer factor.

It is unlikely that the abnormalities found in respiratory function can solely be explained by the patients' smoking history, as there were no correlations between smoking history and the parameters measured or between the smoking history of those patients with and without lung involvement. Infection due to immunosuppression is common in patients with ANCA-associated vasculitis; however, it is unlikely that pneumonia affecting patients could explain the abnormalities found in this study as only three patients suffered from pneumonia during their disease follow-up, only one of whom had lung involvement at presentation. None of the patients had relevant environmental exposure to explain the findings.

Patients with Wegener's granulomatosis appeared to have worse lung disease and AII compared with patients with microscopic polyangiitis; it is unclear from this study why this occurred. Wegener's granulomatosis is characterized by granuloma formation, which may cause greater scarring of the capillary bed compared with the capillaritis characteristic of microscopic polyangiitis. This finding requires confirmation in a larger study.

We used a normal chest X-ray as our definition of no lung involvement; however, a normal chest X-ray does not exclude disease affecting the lungs. Some patients with no lung involvement using this definition had significant abnormalities in lung function. These patients may have had more subtle disease involving the lungs at diagnosis not detected by chest X-ray, resulting in damage; a prospective study is required to address this question.

No other studies have investigated functional capacity and health status in patients with ANCA-associated vasculitis, although it is well recognized that health status remains poor despite successful treatment of disease [7, 20]. The observed relationship between reduced exercise tolerance and health status seen here is well established in other chronic lung diseases, including COPD and bronchiectasis [18, 21]. Pulmonary rehabilitation with exercise training in these conditions has shown improvements in exercise capacity which have correlated with improvements in health status; this is a recognized evidence-based therapy [22]. This study suggests that it is important to identify those patients with ANCA-associated vasculitis who have impaired exercise capacity, as their health status may be improved by programmed exercise, similar to other chronic diseases. This cannot be based on clinical judgement alone as previous lung involvement as defined by a normal chest X-ray was not predictive of exercise capacity. Furthermore, the demonstration that two-thirds (18) of patients had functional aerobic impairment (AII >27%) suggests that exercise capacity may be a useful adjunctive measurement to assess fatigue.

Respiratory and peripheral muscle weakness was correlated significantly with reduced exercise capacity. Indeed the majority of patients cited leg fatigue rather than dyspnoea as a reason for exercise termination. The mechanism for muscle weakness in these patients is unclear as there was no relation to steroid dose, unlike patients with COPD, in whom steroids contribute to respiratory and peripheral muscle weakness [9]. Other diseases that may have a vasculitic component, such as SLE, have also shown impaired respiratory muscle function not associated with steroid use [23]. A recent study of patients with SLE also showing reduced exercise capacity suggested that microangiopathy leading to reduced oxygen delivery to muscle cells was important for the reduced exercise capacity and fatigue observed [17]. Our study suggests that that oxygen diffusion may also be important even in those without previous clinical lung involvement; this is supported by the significant relationship between transfer factor and peak oxygen uptake.

Further studies are required to investigate the mechanisms producing impaired respiratory muscle function in patients with vasculitis. While improvements in muscle function have been attained after pulmonary rehabilitation in patients with COPD, we do not know whether the mechanism of impairment is similar to what occurs in patients with vasculitis or whether respiratory muscle strength may be improved when poor functional status is a result of other mechanisms, such as microangiopathy, as suggested by Keyser et al. [17].

In conclusion, patients with ANCA-associated vasculitis show significant abnormalities of lung function correlating with reduced exercise capacity and health status. All patients with ANCA-associated vasculitis should have formal lung function assessments to assess subclinical disease. The demonstration of reduced exercise capacity and reduced health status in patients with normal lung function also suggests that physiological impairment may be underestimated by measurement of lung function parameters alone. Future research should investigate the role of pulmonary rehabilitation in these patients.

The authors have declared no conflicts of interest.


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Submitted 14 September 2004; revised version accepted 21 December 2004.



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