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(Chest. 2003;124:255-261.)
© 2003 American College of Chest Physicians

Visualization and Functional Consequence of Pulmonary Vascular Impairment in Patients With Rheumatic Diseases*

Hajime Kono, MD, PhD and Shigeko Inokuma, MD

* From the Department of Allergy and Immunological Diseases, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan.

Correspondence to: Shigeko Inokuma, MD, Department of Allergy and Immunological Diseases, Tokyo Metropolitan Komagome Hospital, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8677, Japan; e-mail: inokuma-k{at}komagome-hospital.bunkyo.tokyo.jp


   Abstract
TOP
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Study objectives: Systemic rheumatic diseases impair the vasculature in lungs. The aim of this study was to visualize vascular impairment and determine its consequence on lung function.

Patients and measurements: Seventy-two patients with rheumatic diseases were evaluated by pulmonary function tests, ventilation-perfusion scintigraphy, and thermography of the hands. The ventilation-perfusion mismatch of the lungs was visualized and quantified by calculating the ventilation-perfusion ratio (/) at each pixel. The microvascular impairment in fingers was assessed by the temperature difference between the nail fold and the dorsal hand.

Results: Patients with rheumatic diseases exhibited an increased / that distributed at the periphery of the lungs. The diffusing capacity of the lung for carbon monoxide (DLCO) decreased (mean [± SD], 76.4 ± 27.4% of predicted) relative to the vital capacity (VC) [mean, 88.4 ± 21.8% of predicted; p < 0.01] regardless of the presence or absence of interstitial lung disease (ILD). The distal-dorsal temperature difference showed colder fingers in patients with Raynaud phenomenon (mean temperature, - 0.6 ± 2.1°C) than in those without it (mean temperature, 0.3 ± 1.5°C) and significantly correlated with the ventilation-perfusion mismatch of the lungs both in patients with ILD (p = 0.04) and in those without ILD (p = 0.02). The ventilation-perfusion mismatch of the lungs significantly correlated with the relative reduction in DLCO evaluated by the percent DLCO/percent VC ratio both in patients with ILD (p < 0.01) and in those without ILD (p = 0.02).

Conclusions: These results suggest that the periphery-distributed microvascular impairment in the lungs leads to ventilation-perfusion mismatch that functionally causes a relative reduction in DLCO in patients with rheumatic diseases. The reduction in DLCO relative to VC represents the vascular impairment in the lungs both in patients with ILD and in those without.

Key Words: finger temperature • interstitial lung disease • microvascular disturbance • Raynaud phenomenon • pulmonary diffusion capacity • ventilation-perfusion ratio


   Introduction
TOP
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
Pulmonary involvement is a common feature of rheumatic diseases, with > 70% of systemic sclerosis (SSc) patients having either roentgenographic or pulmonary function abnormalities.1 The pulmonary involvement consists of the following two major manifestations: interstitial lung disease (ILD) and vascular disease. ILD can be detected by high-resolution CT scanning in the early stage of the disease. Vascular disease is evident only in its final stage with development of pulmonary arterial hypertension that often leads to death. The "gold standard" for the diagnosis of pulmonary hypertension is cardiac catheterization. Echocardiography also can detect pulmonary hypertension based on the right ventricular pressure from the tricuspid regurgitation, which correlates well with the catheter-determined pressure. However, methods of detecting vascular impairment in the prehypertension or early pulmonary hypertension stages are not yet available.2 The lack of methods for the detection of early vascular impairment prevents us from understanding the natural history of the disease, and this results in late-phase intervention and poor response to the therapy.

The diffusing capacity of the lung for carbon monoxide (DLCO) indicates the ability of the lungs to transfer gas from inhaled air to the capillaries. A low DLCO suggests the presence of emphysema, ILD, or pulmonary thromboembolism. In a study of 165 patients with SSc,3 20% had an "isolated" reduction in DLCO. A severely reduced DLCO, often isolated, may antedate the development of isolated pulmonary hypertension.4 5 Pronk and Swaak6 reviewed reports of pulmonary hypertension in patients with connective tissue diseases and concluded that the reduction in DLCO in the early phase is a characteristic feature. These findings suggested that the reduction in DLCO relative to lung volumes might indicate an underlying vascular impairment in the lungs that would develop into pulmonary hypertension. However, there may be some problems in the conclusion that the reduction in DLCO can be used as a means of detecting vascular impairment. Those studies included patients with ILD that decreases DLCO. The other problem is that patients with major vessel thromboembolism, which also causes a relative reduction in DLCO, were not excluded from the studies. In addition, if these problems are to be solved, how can we detect the pulmonary vascular impairment at its early stage and does it really lead to the relative reduction in DLCO?

We have developed a semiquantitative ventilation-perfusion scintigraphy that can reveal ventilation-perfusion mismatch.7 The lesion and extent of ventilation-perfusion mismatch were clearly demonstrated by graphically calculated images. We found that patients with rheumatic diseases often reveal a particular pattern other than the segmental or large defects seen in perfusion. The impaired perfusion and subsequent areas of mismatched ventilation-perfusion were predominantly distributed along the periphery of the lungs.7 We hypothesized that the peripheral distribution of perfusion impairment originates from microvascular impairment.

In this study, we confirmed that the peripheral distribution of areas of mismatched ventilation-perfusion in the lungs originates from vascular impairment by showing its correlation with vascular impairment in the fingers. Next, we showed that the microvascular impairment induces ventilation-perfusion mismatch that leads to the relative reduction in DLCO of the lung. Finally, we showed that the microvascular involvement in the lungs can be detected in isolation even in patients with ILDs, based on the relative reduction in DLCO and by ventilation-perfusion scintigraphy.


   Patients and Methods
TOP
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients
The clinical records of all consecutive patients who had been admitted to Tokyo Metropolitan Komagome Hospital from January 1994 to October 2001 with a diagnosis of systemic rheumatic disease were reviewed. The records of patients included the results of pulmonary function tests, ventilation-perfusion scintigraphy, or thermography of the fingers and were studied simultaneously. Exclusion criteria were as follows: obstruction in the large vessel; obstructive lung disease including bronchiolitis; pulmonary infection; pleural effusion; cardiac diseases; peripheral neuropathy; active arthritis in the hands; and a history of cigarette smoking. Seventy-two patients were finally chosen for the study, which included 65 women and 7 men with a mean age of 50 years (SD, 14 years; range, 21 to 79 years) at the time of testing. Chest radiography and CT scanning showed ILD in 37 patients. Thirty-eight patients had Raynaud phenomenon (RP), and 34 patients did not. The diagnoses of these patients are listed in Table 1 .


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  		Table 1.. Diagnoses of the Patients*

 
Pulmonary Function Tests
The vital capacity (VC) was measured by helium dilution techniques. DLCO was measured using the single-breath method (67 patients) or the steady-state method (5 patients). The predicted values for VC, DLCO by the single-breath method, and DLCO by the steady-state method were calculated using the equation developed by Baldwin et al,8 Burrows et al9 and Kanagami et al,10 respectively. The correction of DLCO for hemoglobin concentrations was performed according to the method of Cotes.11 All pulmonary function tests were performed at room temperature, with the patient in a steady-state condition. The data from the pulmonary function tests were assessed as percentages of the predicted values. To assess the reduction in DLCO relative to VC, we used the ratio of the percent DLCO to the percent VC (%DLCO/%VC).5 We could not adopt the DLCO/alveolar volume ratio because DLCO was measured by the steady-state method in five patients.

Thermography of Hands
Thermographic images were obtained using a thermal imaging camera (model 6T67; NEC Corp; Tokyo, Japan). Before the measurement, the patients were acclimatized to 25°C for 30 min in a temperature-controlled room. The temperatures at the dorsum of the metacarpophalangeal (MCP) joint and nail fold of the right second finger were measured. The distal-dorsal difference was calculated by subtracting the temperature of the dorsum of the MCP joint from that of the nail fold.12 If the finger is colder than the dorsum, the distal-dorsal difference is negative.

Ventilation-Perfusion Scintigraphy of Lungs
Ventilation-perfusion scans were performed by an established and highly reproducible method, essentially as described previously.7 Briefly, images of ventilation and perfusion were obtained sequentially with the patient in the supine position by the inhalation of 370 MBq 133Xe gas and an IV bolus injection of 185 MBq 99mTc-macroaggregated albumin, respectively. A ventilation image was obtained when the patient inhaled the gas mixture as deeply as possible and held the breath at the total lung capacity point for 15 s. Immediately after the ventilation study, the perfusion image was taken at the point of total lung capacity while holding the breath for 15 s. The data of dynamic ventilation and perfusion studies were obtained in a 64 x 64 matrix with a digital gamma camera (model GCA90B; Toshiba Medical Systems; Tokyo, Japan), which was equipped with a low-energy, high-sensitivity, parallel-hole collimator. The scintigraphy counting was linear over the range of 133Xe gas and 99mTc-macroaggregated albumin concentrations in the lungs. Washout images were obtained to exclude obstructive lung disease. The data were analyzed with an image processor (model GMS-55U; Toshiba Medical Systems). The ventilation/perfusion ratio (/) for each pixel was calculated from anterior images (Fig 1 , top, A). The whole-lung field was divided into six subregions of interest (ie, bilateral upper, middle, and lower [Fig 1 , bottom, B]). The / of the whole lungs was set to 1.0, and the relative / of each subregion was calculated. The highest / among the six subregions was adopted as the ventilation-perfusion mismatch of the lungs. The highest / in healthy subjects is not greater than 1.25.7



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  		Figure 1.. Ventilation ()-perfusion () scintigraphy and regions of interest. Top, A: / ratio for each pixel (64 x 64 matrix) was calculated from anterior images by dividing the radioactivity count of the ventilation image by that of the perfusion image. Dense staining indicates increased /. Bottom, B: the whole pair of lungs was divided into six subregions. The / of the whole pair of lungs was set to 1.0, and the mean / of each subregion was calculated. In this case, the lowest / was 0.829 for subregion 1 and the highest / was 1.52 for subregion 6. The highest / among the six subregions of interest was adopted as the index of the ventilation-perfusion mismatch of the lung.

 
Criteria for Diagnosis
The diagnosis of RP was based on a typical history of triphasic or biphasic symmetric episodes of discoloration of the fingers after exposure to cold or emotional stimuli. The diagnoses of systemic rheumatic diseases were based on the criteria established by the American College of Rheumatology. Patients who had signs and symptoms that were strongly suggestive of a rheumatic disease but did not fulfill the criteria were diagnosed as having an unclassified connective tissue disease. ILD was diagnosed by careful auscultation and chest radiography, including posteroanterior, lateral, and two oblique views. CT scanning was performed on patients with positive auscultation findings, on those with findings of ILD by chest radiography, or on those with ventilation-perfusion mismatch (highest /, > 1.25) to confirm the absence or presence of ILD.

Statistical Analysis
Values are given as the mean ± SD, unless otherwise specified. We adopted the Student t test or paired t test for the comparison of means in large samples of similar variances. Correlation was measured using the Pearson correlation coefficient and the Fisher r to z. A statistical software package (StatView, version 4.5; Abacus Concepts, Inc; Berkeley, CA) was used for all statistical calculations, and p values of < 0.05 were considered to be significant.


   Results
TOP
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Reduction in DLCO Relative to Lung Volumes
We first evaluated whether patients with rheumatic diseases showed reductions in DLCO relative to VC. The results of pulmonary function tests are listed in Table 2 . The %DLCO was significantly lower than the %VC, regardless of the presence of ILD (p < 0.01). The %VC and %DLCO were significantly lower in patients with ILD than in those without ILD (p < 0.01). However, there was no difference (p = 0.35) in %DLCO/%VC between patients with ILD (mean, 0.838 ± 0.212) and those without ILD (mean 0.889 ± 0.249). These findings indicated that patients with rheumatic diseases have a relatively decreased %DLCO compared with the %VC, and that this relative reduction was not caused by ILD alone.


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  		Table 2.. Pulmonary Function Tests in Patients With or Without ILD*

 
Distal-Dorsal Temperature Difference as a Marker of Vascular Impairment
We used distal-dorsal temperature difference in the fingers to measure systemic microvascular impairment other than that in the lungs.12 RP is a common disorder that is characterized by the intermittent symmetric occurrence of pallor, cyanosis, and rubor of the fingers during or after exposure to cold.13 Although the pathogenesis of RP is not completely understood, it is generally accepted that underlying vascular narrowing and increased vascular reactivity that result from cold exposure.14 RP is considered to be one of the most common clinical manifestations of vascular damage.15 As shown in Figure 2 , the mean distal-dorsal temperature differences were - 0.6 ± 2.1°C in patients with RP and 0.3 ± 1.5°C in those without RP (p = 0.02). The distal-dorsal temperature difference correlated with the temperature of the nail fold (p < 0.01 [data not shown]). These findings confirmed that the distal-dorsal temperature difference can be used as an indicator of vascular disturbance in the fingers.12



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  		Figure 2.. Distal-dorsal temperature differences in patients with or without RP. The distal-dorsal temperature difference is negative when the temperature at the nail fold is lower than that at the dorsum of the MCP joint. The mean distal-dorsal difference in patients with RP (- 0.6 ± 2.1°C) was significantly lower (p = 0.02) than that in patients without RP (0.3 ± 1.5°C). Bars = mean ± SD.

 
Ventilation-Perfusion Mismatch Correlated With Distal-Dorsal Temperature Difference
Figure 1 shows the ventilation-perfusion scans of one patient. The highest / was 1.52 in subregion 6. ILD did not significantly affect the highest / values (patients with ILD, 1.63 ± 0.99; patients without ILD, 1.39 ± 0.36; p = 0.17). The ventilation-perfusion mismatch distributed at the periphery of the lungs in all patients. The increased / was not due to the result of an abnormal ventilation scan, but to impaired perfusion.

We next examined whether the perfusion impairment in the lungs originated from the vascular disturbance. To this end, we compared the ventilation-perfusion mismatch with the distal-dorsal temperature difference in the fingers. The distal-dorsal temperature difference showed a significant correlation with the highest / in patients without ILD (Fig 3 , left, A; p = 0.02; r = - 0.38). This correlation was also observed in patients with ILD (Fig 3 , right, B; p = 0.04; r = - 0.33). These results suggest that the vascular disturbance in the lungs, which is one of the manifestations of systemic vascular impairment, causes the periphery-distributed ventilation-perfusion mismatch.



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  		Figure 3.. The correlation between distal-dorsal temperature difference in a finger and the ventilation-perfusion mismatch. The highest / calculated from ventilation-perfusion scintigraphy images significantly correlated with the distal-dorsal temperature difference in a finger both in patients without ILD (left) and with ILD (right).

 
Ventilation-Perfusion Mismatch Associated With the Relative Reduction in DLCO
We next focused on the functional outcome of the ventilation-perfusion mismatch. Previous studies have suggested that the vascular impairment is associated with the relative reduction in DLCO.4 5 6 Figure 4 shows that the highest / significantly correlates with the %DLCO/%VC both in patients without ILD (Fig 4 , left, A; p = 0.02; r = - 0.40) and those with ILD (Fig 4 , right, B; p < 0.01; r = - 0.59). This result shows that the ventilation-perfusion mismatch caused a relative reduction in DLCO regardless of the presence of ILD. Together with the above results, we concluded that the microvascular disturbance causes ventilation-perfusion mismatch that functionally results in a relative reduction in DLCO in patients with rheumatic diseases.



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  		Figure 4.. Correlation between ventilation-perfusion mismatch and relative reduction in DLCO. The highest / calculated from ventilation-perfusion scintigraphy images significantly correlated with the relative reduction in DLCO calculated as the %DLCO/%VC both in patients without ILD (left) and with ILD (right).

 

   Discussion
TOP
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
The results showed that patients with systemic rheumatic diseases had reduced DLCO relative to VC (Table 2) . The factors that affect DLCO are alveolar volume, thickness of the alveolar capillary membrane, hemoglobin concentration, and the distribution of ventilation relative to perfusion.16 17 The DLCO values measured in this study were adjusted by hemoglobin concentrations to exclude the factor of hemoglobin. Thus, the relative decrease in DLCO in our patients may have been caused by the ventilation-perfusion mismatch or by the alveolar destruction, with or without a honeycomb change. A decreased DLCO was observed in patients with ILD (Table 2) . However, the relative reduction in DLCO, assessed as %DLCO/%VC, was observed both in patients with ILD and in those without ILD, and no statistical difference in the %DLCO/%VC was found between these two groups (Table 2) . This result is consistent with that of Kanengiser et al.18 In their study, the ratio of DLCO to lung volume did not correlate with the severity of idiopathic lung fibrosis. Some pathologic factors other than ILD must have caused the relative reduction in DLCO in patients with systemic rheumatic diseases.

A previous study5 showed that the reduction in DLCO relative to lung volume predicts pulmonary hypertension, which is primarily a vascular disease. The relative reduction in DLCO, expressed as the %DLCO/%VC, was well-associated with the ventilation-perfusion mismatch revealed by scintigraphy and was expressed as the highest / among the six subregions (Fig 4) . The data provided evidence that the relative reduction in DLCO in patients with rheumatic diseases is caused by the ventilation-perfusion mismatch. The mismatch was observed in patients with normal chest radiographic or CT scan findings. Moreover, the mismatch was not due to the abnormal ventilation scintigraphy results, suggesting that impairment in microperfusion, not in ventilation, causes this mismatch in such patients.

The high prevalence of ILD in patients with rheumatic diseases obscured the functional consequence of vascular impairment in the lungs. ILD decreases both the diffusion capacity and lung volumes (Table 2) . Table 2 also shows that the patients with ILD tended to have lower %DLCO/%VC values than did those without ILD, but that the difference was not statistically significant. Moreover, the ventilation-perfusion mismatch was reported in patients with idiopathic pulmonary fibrosis.19 We cannot exclude the possibility that ILD causes the ventilation-perfusion mismatch that leads to the relative reduction in DLCO. This hypothesis should be assessed by comparing ventilation-perfusion scintigraphic findings with CT findings in future studies. However, Figure 3 shows that the ventilation-perfusion mismatch in the lungs is well-associated with the distal-dorsal temperature difference of the fingers both in patients with ILD and in those without. These data suggest that the ventilation-perfusion mismatch is not primarily caused by ILD, but by the microvascular disturbance. One of the novel findings of this study is that the relative reduction in DLCO represents the microvascular disturbance in patients with ILD as well as in those without ILD (Fig 3 , 4) .

We assumed that the microvascular change is systemic in patients with rheumatic diseases. We used RP in this study because it shows an overt vascular impairment that is easily detectable and is associated with cold fingers in patients with rheumatic diseases.12 However, pathophysiologic conditions other than RP that lead to microvasculature impairment in the lungs are known in systemic rheumatic diseases. Microthromboembolism presenting as pulmonary vasculopathy has been reported20 in patients with antiphospholipid syndrome. The distinctive microangiitis that is characterized by acute inflammation and necrosis of the alveolar capillaries, arterioles, and small muscular arteries also has been described.21 Pulmonary veno-occlusive disease has been reported in patients with antiphospholipid syndrome22 or systemic lupus erythematosus.23 In patients with SSc, various vascular changes leading to vessel obliteration have been reported,24 including concentric intimal proliferation, medial hypertrophy, variable degree of myxomatous degeneration, and marked perivascular fibrosis. Intimal thickening of pulmonary arteries, as well as dorsal arteries, has been commonly observed.25 Vasospasm in the pulmonary circulation may be important in the pathogenesis of pulmonary hypertension, although the occurrence of pulmonary vasoconstriction in response to cold remains unclarified, and there are conflicting reports regarding this. The observed ventilation-perfusion mismatch and reduction in DLCO seen in patients in this study may not reflect pulmonary artery vasospasm, the pulmonary RP, because all examinations were carried out under warm conditions without the occurrence of RP.

In summary, we showed that patients with rheumatic diseases have reduced DLCO relative to lung volume, which could be an indicator of vascular impairment in the lungs. The relative reduction in DLCO was caused by ventilation-perfusion mismatch, which correlated with the vascular impairment of fingers both in patients with ILS and in those without. Earlier detection of the microvascular impairment in patients with rheumatic diseases would lead to an earlier intervention of pulmonary hypertension and will improve the response to therapy.


   Acknowledgements
 
The authors thank Dr. Kenzo Suzuki for ventilation-perfusion imaging.


   Footnotes
 
Abbreviations: DLCO = diffusing capacity of the lung for carbon monoxide; %DLCO/%VC = percent diffusing capacity of the lung for carbon monoxide to the percent vital capacity ratio; ILD = interstitial lung disease; RP = Raynaud phenomenon; MCP = metacarpophalangeal; SSc = systemic sclerosis; VC = vital capacity; / ratio = ventilation/perfusion ratio

Received for publication June 28, 2002. Accepted for publication December 3, 2002.


   References
TOP
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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