Marchand-Adam et al
ERJ-01496-2007 R1
Online data supplement
short and long-term response to corticosteroid
therapy in chronic beryllium disease
Sylvain MARCHAND-ADAM, MD, Aïcha EL KHATIB, MSc, PhD, François GUILLON,
MD, PhD, Michel Williams BRAUNER, MD, Christine LAMBERTO MD, Virginia
LEPAGE MD, Jean-Marc NACCACHE MD and Dominique VALEYRE, MD
Marchand-Adam et al
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Methods
Exposure to Be
The available data (mainly industrial hygiene data) did not allow the reconstruction of
the historical exposures of each patient. Beryllium exposure was then assessed using two area
sampling data reports for six patients. They worked all in the same smelter. One of them was
a bystander. The two others worked in different plants where exposure monitoring was not
realized. Therefore, data from similar factories were used to estimate their beryllium
exposure. It was then classified according to its assumed intensity in three levels : high when
the beryllium exposure intensity may have exceeded the 2 µg/m3 standard at least once
through the work history ; medium when it never exceeded this standard but was probably
higher than 1 µg/m3 ; and low for an exposure intensity always below 1 µg/m3.
Pulmonary function test
Slow vital capacity (VC) and total lung capacity (TLC) were recorded within a body
plethysmograph, and FEV1/VC from flow-volume curve. The carbon monoxide diffusing
capacity (DLCO) and carbon monoxide transfer coefficient (Ka) were measured by the single
breath method, according to the recommendations of the European Respiratory Society (E1).
We used the mean of at least two reproducible measurements with an interval of four minutes
between each set. Results were corrected for subject’s hemoglobin and carboxyhemoglobin
concentration. Result where expressed as percent predicted values (E2).
Relapse study design
Relapse was considered in the presence of new CBD manifestations (dyspnea, cough,
fever…) following a sustained (longer than 3 months) improvement of symptoms.
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Corticosteroid schedule was then increased to the next upper dosage sufficient to obtain again
control of CBD. This last dosage was considered as the threshold of CBD control.
For those who relapsed, we compared data (i) before relapse (4-12 mo), (ii) at the time
of relapse, and (iii) following a new increase of treatment (4-12 mo).
HRCT scores
All patients underwent a high-resolution computer tomography (HRCT) of the lung at
baseline, after 4 to 12 months of corticosteroid therapy and at the end of the study. At
relapses, HRCT were often available. They were blinded and presented randomly for analysis.
A chest radiologist (MWB) and a pneumologist (SMA) interpreted them simultaneously. The
two observers established easily a consensus about the quantification of lesions. Pulmonary
abnormalities were evaluated as for presence, number, extent and distribution. Opacities, like
ground glass opacities, micronodules, nodules and alveolar consolidations were considered as
active inflammatory granulomatosis lesions and quantified in active lesion score ; while
opacities, like linear opacities, traction bronchiectasia, lobular distortions, bulla formations,
cysts and honeycombings were considered as fibrotic lesion expressions and quantified in
fibrosis lesion score. These two patterns were scored separately in six areas of the lung
defined as follows : the upper zones are above the level of the carina ; the middle zones,
between the level of the carina and the level of the inferior pulmonary veins ; and the lower
zones, under the level of the inferior pulmonary veins. Opacity intensity on thin section
HRCT was scored semi-quantitatively, according to four basic categories : 0 = normal, 1 =
slight, 2 = moderate, 3 = advanced, to yield a total score of parenchymal opacities (total : 0–
18).
Results
Relapses after decrease of corticosteroids
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Seven of 8 patients presented clinical relapses after initial response. Eighteen relapses
were observed. One patient did not relapse but he was treated for only 26 months at the end of
study. The first relapse always occurred after decreasing the corticosteroid doses (17 mg/d [5
to 50 mg/d]. The three patients with Glu69 homozygosity presented eleven of eighteen
relapses.
Clinical relapse was accompanied with significant pulmonary function decrease which
was characterized by a VC decrease (-9% of predicted value [0 to –23%], p<0.01) (Fig. Z1a).
The median DLCO was reduced by -7% of predicted value too [+2 to –19%] (p<0.01, Fig.
Z1b) and was associated with PaO2 decrease (p<0.05, Fig. Z1c). At relapse time, the SACE
level was increased in 9 of 13 cases (p<0.01) (Fig. Z1d). Ten HRCT were available at the
time of relapses for 6 patients. All relapses were accompanied by an increase of the active
lesion score (Fig. Z1e).
A new corticosteroid increase ensured clinical improvement. The pulmonary function
returned to the previous level (Fig. Z1a, Z1b, and Z1c) and SACE to a normal level (Fig.
Z1d). HRCT showed a decrease of the active lesion score (Fig. Z1e).
These results suggested that relapses were linked to re-activation of granulomatosis
inflammation secondary to steroid dose reduction.
To our knowledge, the current study is the first one to investigate the relapse in CBD
monitoring. SACE and active lesion score re-increased at the time of clinical relapses evoking
more the granulomatosis inflammation re-emergence than the fibrosis spread. SACE and
active lesion score can be used for relapse screening. Relapses occurred during tapering the
steroid dose. That may be due to beryllium particles being cleared very slowly from the lungs,
despite the triggering of both the innate and the acquired immune responses (E3). This
beryllium weak elimination may explain prolonged corticosteroid needs.
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References
E1.
Cotes JE, Chinn DJ, Reed JW, and Hutchinson JE. Experience of a standardised
method for assessing respiratory disability. Eur Respir J 1994; 7: 875-80.
E2.
European Coal and Steel Community. Standardised lung function testing. Bull Eur
Physiopathol Respir 1983; 19: 1-93.
E3
Hart BA, Harmsen AG, Low RB, and Emerson R. Biochemical, cytological, and
histological alterations in rat lung following acute beryllium aerosol exposure. Toxicol Appl
Pharmacol 1984; 75: 454-65.
Figures
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Figure Z1
Responses to corticosteroid during CBD relapses.
Slow vital capacity (VC, panel A), carbon monoxide diffusion capacity (DLCO, panel B),
PaO2 (in mmHg, panel C) and SACE (panel D) before, at the time of clinical relapse and after
(n=18 relapses). VC, DLCO and SACE were expressed as percentage of predicted values (%
of pred. values). Quantification of lesions on ten HRCT of patients with CBD before, at the
time and after clinical relaspe (panel E and F). Opacities suggesting inflammatory
granulomatosis (panel E : ground glass opacities, micronodules and nodules) and fibrosis
lesions (panel F: linear opacity, traction bronchiectasia, lobular distortion, bulla formation,
cysts and honeycombing) were scored separately. The severity was scored in six pulmonary
areas according to four basic categories : 0 = normal, 1 = slight, 2 = moderate, 3 = advanced.
Closed circles : patients with Glu69 homozygosity (n=11 relapses). Open circles : patients
without Glu69 homozygosity (n=7 relapses). Individual values and median (bar). †, p < 0.05
compared with the time of relapse.