BRONCHOALVEOLAR LAV AGE IN MIXED

British Journal of Rheumatology
1996;35:978-982
BRONCHOALVEOLAR LAV AGE IN MIXED CRYOGLOBULINAEMIA
ASSOCIATED WITH HEPATITIS C VIRUS
P. MANGANELLI, F. SALAFFI,* S. SUBIACO,t M. CAROTTI,* C. CERVINI,* G. CONSIGLI.J
M. MAJORI§ and A. PESCI§
/ / Divisions Medica e Reumatologia, Azienda Ospedaliera di Parma, *Istituto Policattedra di Patologia e Clinica
deirApparato Locomotore, University di Ancona, ^Divisions di Pneumologia, USL 5, Ospedale di Jesi, %Servizio
di Broncologia, Ospedale Rasori, Azienda Ospedaliera di Parma and§Clinica Malattie dell'Apparato Respiratorio,
Universita di Parma, Italy
SUMMARY
In order to evaluate the presence of an inflammatory process of the lower respiratory tract in patients with mixed
cryoglobulinaemia (MQ associated with hepatitis C virus (HCV), bronchoalveolar lavage (BAL) was performed in 16
non-smoking females free of clinical pulmonary symptoms and with normal chest roentgenograms. Pulmonary function tests
including diffusion capacity for carbon monoxide (DLCO) were also carried out. Thirteen healthy subjects were evaluated as
the control group. Patients with MC had a lower percentage of alveolar macrophages (75% vs 92%, P = 0.001) and a higher
percentage of lymphocytes (19.7% vs 7%, P = 0.001) than healthy controls. The percentage of CD3+ lymphocytes was higher
in MC patients than in controls (86.5% vs 70%, P = 0.004). No significant differences in the percentage of CD4 + , CD8 + and
CD 19+ lymphocytes, neutrophils and eosinophils were found. Pulmonary function tests showed significantly lower values of
forced expiratory flow (FEF) 25-75 (P = 0.05) and DLCO (P = 0.05) in MC patients than in healthy controls. No correlations
between BAL results and pulmonary function tests were found. The 5 yr follow-up of five patients did not demonstrate
deterioration in lung function. Thus, BAL results indicate a subclinical T-lymphocytic alveolitis in MC HCV+ patients that
is not associated with a risk of deterioration in lung function.
KEY WORDS:
Mixed cryoglobulinaemia, Hepatitis C virus, Bronchoalveolar lavage, Lymphocytic alveolitis.
respiratory tract in a small number of MC patients
without clinical and radiological evidence of lung
disease by bronchoalveolar lavage (BAL) [12].
In the present study, we have extended the
pulmonary evaluation to a larger series of patients with
MC and report on the 5 yr follow-up of the previously
studied patients. The possible role of HCV infection in
the pathogenesis of lung involvement in MC is also
discussed.
CRYOGLOBULINAEMIA is a condition characterized by
the presence in the serum of one or more immunoglobulins which precipitate in the cold and redissolve on
re-warming [1]. According to Brouet et al. [2],
cryoglobulins can be subdivided into three groups: type
I, comprised of an isolated monoclonal immunoglobulin; type II, mixed cryoglobulins (MC) with a
monoclonal component; type III, composed only of
polyclonal immunoglobulins.
In the past few years, a striking association between
hepatitis C virus (HCV) infection and MC has been
documented [3-5], and the possible pathogenetic role of
HCV has been supported by the demonstration of viral
genomic sequences in sera, bone marrow and
peripheral blood mononuclear cells of MC patients
[3, 6, 7].
Although pulmonary symptoms are usually absent
or moderate, functional test results pointing to small
airways disease may be abnormal [8,9]. Also, a
decrease in diffusing capacity and roentgenographic
signs of interstitial lung involvement have been
reported [8, 9]. Moreover, in two cases of MC adult
respiratory distress syndrome [10] and bronchiolitis
obliterans organizing pneumonia [11] have been
described.
In a previous report, we documented the presence of
a subclinical inflammatory process of the lower
PATIENTS AND METHODS
Patients
BAL was performed in 16 female patients with MC
who had never smoked, with a mean age of
53.1 ± 2.4 yr and a mean disease duration of 47 ± 4.8
months (Table I). All patients were not affected by
other respiratory diseases such as asthma and had
normal findings on chest roentgenograms. The
diagnosis of MC was based on the presence of the triad:
purpura, arthralgias and weakness associated with
dosable mixed cryoglobulins in serum. All patients had
normal haematological and biochemical parameters,
except for four, who showed liver enzyme alterations.
Three patients had peripheral sensitive neuropathy,
confirmed by electrophysiological studies and sural
nerve biopsy in one of them. BAL was carried out after
at least a 3 week washout period from therapy, with
prednisone and/or colchicine, except in one patient,
who continued colchicine 1 mg/day. Patients with
cryoglobulinaemia associated with haematological,
autoimmune disorders, acute and chronic infectious
diseases other than HCV infection, and serious medical
Submitted 10 November 1995; revised version accepted 16 April
1996.
Correspondence to: A. Pesci, Clinica Malattie dell'Apparato
Respiratorio, Via Rasori 10, 43100 Parma, Italy.
© 1996 British Society for Rheumatology
978
979
MANGANELLI ET AL.: BAL IN MIXED CRYOGLOBULINAEMIA
illness were excluded from the study. The BAL
control group comprised 13 healthy volunteers (eight
men and five women, mean age 33.8 + 3.1 yr, nonsmokers).
The study protocol had the approval of the local
ethics committee. Each individual gave informed,
written consent before undergoing the bronchoscopy
procedure.
Anti-HCV antibodies
All sera were kept at — 80°C until assayed for
anti-HCV antibodies, according to the manufacturer's
instructions, using a second-generation enzyme-linked
immunosorbent assay (ELISA; Chiron-Ortho Diagnostics, Emeryville, CA, USA) and confirmed by a
second-generation recombinant immunoblot assay
(RIBA; Chiron-Ortho).
Pulmonary function tests (PFTs)
Spirometry was performed prior to bronchoscopy
using a Morgan automated pulmonary function
system (Spiroflow; Morgan, Kent). The best of
three expiratory efforts was analysed and slow vital
capacity (SVC), total lung capacity (TLC), forced
expiratory volume in 1 s (FEVi) and forced expiratory
flow (FEF) 25-75 were recorded. Diffusion capacity
for carbon monoxide (DLCO) was measured by
the single-breath technique (Spiroflow; Morgan,
Kent). The predicted normal values used were those
from the European Community for Coal and Steel
(CECA) [13]. In five patients, PFTs were repeated after
a 5 yr follow-up. During this interval period, these
patients were not treated with corticosteroids.
Bronchoscopy
In all subjects, the upper airways were anaesthetized
by 4 ml of lidocaine at 2%.
Further lidocaine (1%) was administered to the
lower airways, to suppress coughing after introduction
of the flexible fibre optic bronchoscope (Olympus
IT 10, Tokyo, Japan). The bronchoscope was wedged
into a segment of the right middle lobe, and three 50 ml
aliquots of sterile saline solution, warmed at 37°C, were
infused. Fluid was gently aspirated immediately after
each aliquot was introduced and collected in a sterile
container.
BAL processing
After recovery, BAL fluid was strained through a
monolayer of surgical gauze to remove mucus. The
fluid was immediately centrifuged at 800 r.p.m. for
10 min at +4°C. The cell pellet was washed twice with
phosphate-buffered saline solution (without Ca2+ and
Mg2*). Cytocentrifugates (Labofuge AE, Heraeus,
Germany) were stained by the May-GrunwaldGiemsa method. The differential cell count of
macrophages,
lymphocytes,
neutrophils,
and
eosinophils was made under light microscopy at
x 1000, by counting ~ 300 cells in random fields. In the
supernatant, albumin and IgG were determined by
single radial immunodiffusion with immunoplates (LC
Partigen, Behringwerke AG, Marburg, Germany).
Albumin was expressed in mg/ml and IgG as the
IgG/albumin ratio.
Analysis of lymphocyte subsets
Specific binding of monoclonal antibodies (MAb)
was analysed by direct immunofluorescence according
TABLE I
Clinical characteristics of 16 patients with mixed cryoglobulinaemia and 13 healthy control subjects
Number Age(yr)
1
2
3
4
5
6
7
g
9
10
11
12
13
14
15
16
x mcwn
S.B.
56
59
52
52
50
66
21
53
59
60
48
49
51
54
61
60
53.1
2.4
Control subjects
x mean
33.8
3.1
ss.
Sex
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
5 F/8 M
Disease
duration Cry cent
Smoke (months)
%
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
48
15
60
32
24
24
57
24
36
60
84
60
48
72
48
60
47
4.8
3
30
5
10
5
20
5
5
36
11
15
8
17
-
-
3
8
10
11.9
2.4
Cryoglobulins
HCV
IgG/IgM-K
IgG/IgM-K
IgG/IgM-K
IgG/IgM
IgG/IgM
IgG/IgM-K
IgG/IgM
IgG/IgM-K
IgG/IgM-K
IgG/IgM-K
IgG/IgM-K
IgG/IgM-K
IgG/IgM-K
IgG/IgM-K
IgG/IgM-K
IgG/IgM-K
positive
positive
positive
positive
positive
positive
positive
positive
positive
positive
positive
positive
positive
positive
positive
positive
-
negative
FEV,
FEF 25-75
SVC
TLC
% pred.
% pred. % pred. % pred.
98
107
122
102
122
117
108
126
121
96
121
109
127
128
104
121
114.3
2.6
99
113
121
105
121
107
98
106
100
90
102
104
111
117
96
116
106.6
2.2
103
105
124
98
118
123
126
113
108
95
107
123
127
126
107
109.3
2.1
101.4
3.1
DLCO
% pred.
2.6
82
100
111
88
111
112
136
66
63
75
84
79
90
92
82
65
89.7
5
92
83
92
73
71
88
62
75
85
65
87
84
89
85
84
76
80.6
2.3
106.1
2.5
98.5
3.3
101.6
2.7
no
113.3
SVC, slow vital capacity; TLC, total lung capacity; FEVi, forced expiratory volume in 1 s; FEF 25-75, forced expiratory flow; DLCO, diffusion
capacity; % pred., per cent of predicted value.
980
BRITISH JOURNAL OF RHEUMATOLOGY VOL. 35 NO. 10
TABLE II
Bronchoalveolar lavage data of 16 patients with mixed cryoglobulinaeinia and 13 healthy control subjects
Number
Cells/ml
x KV
Ma. %
Ly. %
Ne. %
Eo. %
CD3+ %
I
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Median
Range
232
208
192
146
255
185
210
164
200
179
172
124
113
250
50
100
182
50-255
82
72.5
95.5
50
93
77.5
82.9
70
70
66
60
88
90
43
62
80
75
43-95.5
17.5
19.5
4
34
6.5
19
15.6
26
24
29
37
12
8
57
33
20
19.7
4-57
0.5
6.5
0.5
15
0.5
3.5
.4
4
6
2
2
0
0
1.5
0
1
0
0
0.1
0
0
1
1
0
1
0
3
0
0
0-3
98
91
94
86
85
75
95
89
90
89
72
69
68
87
78
85
86.5
68-98
Control subjects
1
160
2
200
3
240
4
170
5
120
160
6
7
180
8
120
110
9
10
120
11
160
12
210
60
13
Median
160
60-240
Range
P
NS
94
92
92
90
92
95
93.5
85.5
91.5
93.8
84.8
94.5
87.8
92
84.8-95
0.001
6
7
7
9
8
5
6
12
7.5
4.8
13.5
3.6
II
7
3.6-13.5
0.001
0
0
0
0
0
0
0
0.5
0.1
0.2
0.3
0
0.4
0
0-0.5
NS
51
70
81
94
80
0
2
0
1.7
0-15
0
1
1
0
0
0.5
2
0.8
1.1
1.4
1.8
0-2
NS
55
70
63
70
64
62
81
73
70
51-94
0.004
CD8+ %
Albumin
(mg/ml)
IgG/albumin
ratio
96
79
68
61
75
38
43
51
60
73
48
47
44
27
54
66
57
27-96
10
18
18
28
24
52
45
37
33
15
30
27
30
52
25
18
27.5
10-52
7.45
6.24
3.15
6.89
6.89
8.9
3.75
7.67
7.01
8.03
6.91
3.15
6.07
6.79
3.75
7.21
6.89
3.1-8.9
0.27
0.34
0.42
0.28
0.39
0.31
0.71
0.34
0.12
0.75
0.42
0.28
0.27
0.24
0.55
0.4
0.34
0.12-0.75
41
50
60
70
53
52
53
49
54
48
40
20
32
48
43
34
36
36
33
27
41
21
23
34
20-48
NS
0.54
2.18
4.75
2.46
1.56
1.22
10.87
7.55
5.6
15.51
3.15
3.75
7.52
3.75
0.54-15.5
NS
0.2
0.1
0.1
0.54
0.4
0.24
0.28
0.25
0.23
0.28
0.55
0.41
0.34
0.28
0.1-0.55
NS
CD19+ % CD4 + %
nd
nd
nd
nd
nd
nd
1
7
2
4
3
1
3
6
4
2
3
1-7
1
3
2
1
3
3
1
4
7
2
4
1
2
2.61
1-7
NS
55
60
51
53
41-70
NS
Ma., macrophages; Ly., lymphocytes; Ne., neutrophils; Eo., eosinophils; nd, not done.
to standard methods recommended by the BectonDickinson Monoclonal Center (Mountain View, CA,
USA) using flow cytometry (FACScan, Becton
Dickinson).
Briefly, 100/il of BAL cells (1 x 103 cells) were
incubated in the presence of saturating concentrations
of fluorescein- or phycoerythrin-conjugated MAb at
room temperature for 20 min. Erythrocytes were lysed
by adding 2 ml of lysing solution for 10 min. Cells were
washed twice with phosphate-buffered saline containing 2% fetal calf serum and 0.1% sodium azide.
Cytofluorimetric analysis was performed by imposing
an electronic gate on forward-scatter (FSQ and
side-scatter (SSC) dot plots for the lymphocyte
fraction. The number of immunofluorescence-positive
cells was determined in 10 000 analysed cells. Specific
binding of MAb was controlled by subtraction
of isotype-matched mouse immunoglobulins. MAb
against CD3 (T cells), CD4 (T helper cells), CD8 (T
suppressor-cytotoxic cells) and CD 19 (B cells) were
purchased from Becton Dickinson. Results were
expressed as positive per cent relative to an isotype
antibody.
Data analysis
Group data were expressed as medians and range, or
means ± s.E. when appropriate. Comparisons between
BAL data of MC patients and control subjects were
made using the Mann-Whitney f/-test. In five MC
patients, PFTs were compared before and after a 5 yr
follow-up using Wilcoxon's analysis for paired data.
The Spearman rank test was used to examine the
association of clinical parameters with BAL data; we
accepted a P value of <0.05 as indicating significance.
RESULTS
Pulmonary function tests
Studies of pulmonary function (Table I) showed a
significant reduction in FEF 25-75 (P = 0.05) and
DLCO (P = 0.05) in patients with MC relative to
normals when expressed as a per cent predicted of
normal values. However, values for both remained
within the normal range for MC patients (FEF 25-75
89.7 ± 5% of predicted values; DLCO 80.6 ± 2.3% of
predicted values). In contrast, lung volumes were not
significantly different in MC patients and healthy
controls. FEF 25-75 values were unchanged after
MANGANELLI ET AL.: BAL IN MIXED CRYOGLOBULINAEMIA
salbutamol inhalation, indicating a non-reversible
defect of the small airways. Lung function tests were
not significantly changed in five patients (patients 2-6)
when PFTs were repeated 5 yr after BAL and baseline
functional evaluation (SVC % predicted: 114 ± 4
before and 126.6 ± 7 after; TLC % predicted:
113.4 ±3.3 before and 123.3 ± 6.3 after; FEV1 %
predicted: 113.6 ±5.1 before and 122.2 ± 7.9 after;
FEF 25-75 % predicted: 104.4 ± 4.6 before and
109.4 ± 7 after; DLCO % predicted: 81.4 ± 4.1 before
and 85.0 ± 2.9 after).
BAL analysis
Analysis of BAL fluid (Table II) showed a
non-significant increase in the total cells recovered
from MC patients relative to normals. In comparison
with normal controls, differential cell counts revealed
a significant reduction in the percentage of alveolar
macrophages (P = 0.001) and a significant increase in
the percentage of lymphocytes (P = 0.001) in MC
patients. In contrast, the percentage of neutrophils and
eosinophils was not significantly different between the
two groups of subjects. The distribution of lymphocyte
populations showed a significantly higher percentage of
CD3+ cells in MC patients than in normal controls
(P = 0.004), whereas the percentage of CD4 +, CD8 +
and CD19 + cells was not significantly different.
The increase in albumin and the IgG/albumin ratio
in MC patients was not statistically significant.
No correlations between BAL results and pulmonary
function tests were found (data not shown).
DISCUSSION
The results of this study show the presence of a
subclinical inflammatory process of the lower respiratory tract, as assessed by BAL, mainly characterized by
the presence of T lymphocytes, which was not
associated with deterioration in lung function over
time.
The absence of clinical and radiographic manifestations of pulmonary disease did not support the
performance of lung biopsies. However, the correlations between inflammatory and immune effector
cells present within the lung parenchyma at open lung
biopsy with those recovered by BAL in interstitial lung
disease [14] suggest that the increased lymphocytes in
BAL obtained from our MC patients reflect their
accumulation in the lung parenchyma.
Lymphocytic alveolitis observed in MC patients fits
nicely with the finding of B-lymphoid aggregates in
bone marrow and liver biopsies which have been
reported in other series of MC patients [15]. However,
the predominance of T cells and the not significant
increase in B cells in BAL fluid of our MC patients
suggests an inflammatory process rather than a
lymphoproliferative disorder of the lower respiratory
tract.
Immune complex deposition is the primary event in
tissue injury which occurs in MC [16]. Clinical [17] and
experimental [18] evidence indicates a role for immune
complexes in the pathogenesis of interstitial inflamma-
981
tory diseases of the lung. However, the absence of a
significant increase in neutrophils and albumin in BAL
fluid obtained from our MC patients is atypical for
immune complex-mediated lung disease. This may be
due to a lesser degree of immune complex deposition.
Alternatively, it may suggest that other factors are
responsible for inducing the lymphocytic alveolitis
found in MC. In this regard, the lymphotropism of
HCV, as found in patients with HCV-related chronic
hepatitis [19] and MC [6, 7], raises the question of
whether this virus plays a role in the accumulation of
T cells in the alveolar spaces in MC HCV+ patients.
A possible role of HCV in causing a lymphocytic
alveolitis with increased activated T cells in patients
with chronic hepatitis C has recently been suggested
[20].
In addition, a similar role of HCV in the
pathogenesis of idiopathic pulmonary fibrosis has been
supported by Japanese authors [21], but not confirmed
by British investigators [22]. However, the role of HCV
in the pathogenesis of lymphocytic alveolitis in patients
affected by MC or chronic hepatitis is unknown.
PFTs performed in this series of MC patients
demonstrated a mild but significant reduction in FEF
25-75 and DLCO relative to normals, although mean
values remained within the normal range, and this
control group was not age and sex matched. PFTs
compatible with small airways disease and a decrease
in diffusing capacity in MC have been previously
reported by other authors [8, 9]. In a previous report,
we found similar PFT results in patients with Sjogren's
syndrome free of clinical pulmonary symptoms and
with normal chest X-ray [23]. The degree of
inflammation of the lower respiratory tract, as assessed
by BAL, did not correlate with measurements of lung
function and was not predictive of deterioration in lung
function over time.
An absence of a correlation between lymphocytic
alveolitis and changes in lung function has also been
found in patients with primary Sjogren's syndrome
who were followed over a 12 month time interval [24].
Similar results have recently been reported by a
long-term follow-up study of patients affected by
collagen vascular diseases, such as systemic lupus
erythematosus [25] and rheumatoid arthritis [26], where
lymphocytic alveolitis was documented [24, 27].
In this context, Wallaert et al. [24] noted increases in
BAL lymphocytes or neutrophils, or both, in 29 of 61
patients (48%) with a spectrum of collagen vascular
disease, even though none had pulmonary symptoms.
Similar lymphocytic alveolitis has been described in
Crohn's disease [28] and in primary biliary cirrhosis
[29] (10 out of the 18 patients and six out of the 12
patients, respectively).
In contrast, the subclinical neutrophilic alveolitis
present in other collagen vascular diseases, such as
systemic sclerosis, was frequently associated with the
deterioration of pulmonary function tests in untreated
patients [24].
In conclusion, our study shows a subclinical lung
inflammation in MC HCV + patients, characterized by
982
BRITISH JOURNAL OF RHEUMATOLOGY VOL. 35 NO. 10
T-lymphocytic alveolitis in BAL, that does not seem to
be predictive of lung function deterioration. Further
studies are needed to clarify the possible role of HCV
in the pathogenesis of the alveolitis associated with this
disease.
15.
ACKNOWLEDGEMENT
Partly supported by a grant from the Ministero
deH'Universita e Ricerca Scientifica.
16.
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